Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

ABSTRACT

Provided are methods and intermediates for preparing diastereomerically pure phosphoramidate prodrugs of nucleosides of Formulas Ia and Ib: 
                         
The compounds of Formula Ia and Ib are useful for the treatment Hepatitis C infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application of InternationalApplication No. PCT/US2011/044581, filed Jul. 19, 2011, which claims thebenefit of U.S. Provisional Application No. 61/365,621, filed Jul. 19,2010. The contents of the aforementioned applications are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates generally to methods for preparing compounds withantiviral activity, most particularly to prodrugs of inhibitors ofhepatitis C virus RNA-dependent RNA polymerase.

BACKGROUND OF THE INVENTION

The hepatitis C virus (HCV) is a leading cause of chronic liver diseaseworldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000) and may lead tohepatic fibrosis, cirrhosis and hepatocellular carcinoma (Cale, P.,Gastroenterolgy Clin. Biol. 2009, 33, 958). A significant focus ofcurrent antiviral research is directed toward the development ofimproved methods of treatment of chronic HCV infections in humans (DiBesceglie, A. M. and Bacon, B. R., Scientific American, October: 80-85,(1999); Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1-20; Maradpour,D.; et al., Nat. Rev. Micro. 2007, 5(6), 453-463). A number of HCVtreatments are reviewed by Bymock et al. in Antiviral Chemistry &Chemotherapy, 11:2; 79-95 (2000).

Currently, there are primarily two antiviral compounds, ribavirin, anucleoside analog, and interferon-alpha (α) (IFN), which are used forthe treatment of chronic HCV infections in humans. Ribavirin alone isnot effective in reducing viral RNA levels, has significant toxicity,and is known to induce anemia. The combination of IFN and ribavirin hasbeen reported to be effective in the management of chronic hepatitis C(Scott, L. J., et al. Drugs 2002, 62, 507-556) but less than half thepatients given this treatment show a persistent benefit. Other patentapplications disclosing the use of nucleoside analogs to treat hepatitisC virus include WO 01/32153, WO 01/60315, WO 02/057425, WO 02/057287, WO02/032920, WO 02/18404, WO 04/046331, WO2008/089105 and WO2008/141079but additional treatments for HCV infections have not yet becomeavailable for patients. Therefore, drugs having improved antiviral andpharmacokinetic properties with enhanced activity against development ofHCV resistance, improved oral bioavailability, greater efficacy, fewerundesirable side effects and extended effective half-life in vivo (DeFrancesco, R. et al. (2003) Antiviral Research 58:1-16) are urgentlyneeded.

RNA-dependent RNA polymerase (RdRp) is one of the best studied targetsfor the development of novel HCV therapeutic agents. The NS5B polymeraseis a target for inhibitors in early human clinical trials (Sommadossi,J., WO 01/90121 A2, US 2004/0006002 A1). These enzymes have beenextensively characterized at the biochemical and structural level, withscreening assays for identifying selective inhibitors (De Clercq, E.(2001) J. Pharmacol. Exp. Ther. 297:1-10; De Clercq, E. (2001) J. Clin.Virol. 22:73-89). Biochemical targets such as NS5B are important indeveloping HCV therapies since HCV does not replicate in the laboratoryand there are difficulties in developing cell-based assays andpreclinical animal systems.

Inhibition of viral replication by nucleosides has been extensivelystudied (De Clercq, E. (2001) J. Clin. Virol. 22:73-89) includingnucleosides that inhibit RdRp. Generally, the antiviral activity ofthese nucleosides are attributed to the conversion of the nucleosides totheir nucleoside triphosphates (NTPs) which act as inhibitors of DNA andRNA polymerases or as chain terminators following incorporation into thelengthening viral DNA or RNA strand. However, many NTPs lack adequatespecificity for viral polymerases compared to host polymerases and, as aresult, cause substantial toxicity. This has led to efforts to modifythe core structures of nucleosides to achieve higher selectivity butmany of the structural modifications have simultaneously compromised NTPproduction in the cells (Yamanaka, Antimicrob. Agents Chemother. 1999:190-193).

The poor conversion of the nucleoside to NTP can often be attributed tothe inability of nucleoside kinases to convert the nucleoside to thenucleoside 5′-monophosphate (NMP). NMP prodrugs have been used to bypasspoor nucleoside kinase activity (Schultz, Bioorg. Med. Chem. 2003, 11,885). Among these prodrugs, NMP phosphoramidates have been reported toincrease intracellular concentrations of NTP compared to the nucleosidealone (McGuigan, J. Med. Chem. 1993, 36, 1048-1052). However, these NMPprodrugs are substrates for esterases and phosphodiesterases in theblood and other body tissues which can cleave the prodrug to a chargedmolelcule or to the nucleoside, respectively. The charged molecule isthen impermeable to the target organ or cell and the nucleoside ispoorly phosphorylated intracellularly.

The development of a highly effective, non-toxic NMP prodrug is largelyan unpredictable trial and error exercise requiring the balancing of thestability of the NMP prodrug in blood with the ability of the prodrug toreach a target organ or cell, be absorbed or actively taken up by thetarget cell, being efficiently cleaved to the NMP intracellularly andsubsequently converted to a NTP that is selective for inhibiting theviral polymerase (Perrone, J. Med. Chem. 2007, 50, 1840-49; Gardelli, J.Med. Chem. 2009, 52, 5394-5407). For the case of an orally effectiveRdRp inhibitor for treating HCV infection, the NMP prodrug would need tobe chemically stable to the conditions of the upper intestinal tract, beefficiently absorbed from the intestinal tract, survive the manyesterases of the intestinal cells and blood, be efficiently extracted bythe hepatocytes, and be cleaved to the NMP and subsequently converted toa NTP in hepatocytes that is specific for inhibiting the HCV NS5Bpolymerase. Notably, the anti-HCV activity of phosphate prodrugs canmarkedly depend upon the chirality of the phosphorous in the prodrug(Gardelli, J. Med. Chem. 2009, 52, 5394-5407; Meppen, Abstracts ofPapers, 236th ACS National Meeting, Philadelphia, Pa., United States,Aug. 17-21, 2008 (2008), MEDI-404.).

Babu, Y. S., WO2008/089105 and WO2008/141079, discloses ribosides ofpyrrolo[1,2-f][1,2,4]triazine nucleobases with antiviral, anti-HCV, andanti-RdRp activity.

Butler, et al., WO2009132135, disclose 1′ substituted ribosides andprodrugs comprising pyrrolo[1,2-f][1,2,4]triazine nucleobases which haveanti-HCV and anti-RdRp activity but does not disclose species of the3′-O-acylated derivatives of those ribosides or the expected propertiesof such derivatives. Cho, et al., U.S. 61/353,351, discloses3′-O-acylated 1′ substituted ribosides phosphate prodrugs comprisingpyrrolo[1,2-f][1,2,4]triazine nucleobases that have anti-HCV activitythat are efficiently delivered to the liver after oral administration.The efficient delivery of the prodrugs to the liver is dependent on thechirality of the phosphorous prodrug.

In view of the importance of anti-HCV therapeutics that are NMP prodrugswith chiral phosphorous atoms such as those described by Cho, et al.,Gardelli, et al., Perrone et al., and Meppen, et al., new efficientmethods of producing chiral phosphates of these prodrugs are needed.

SUMMARY OF THE INVENTION

Provided are methods for preparing compounds that inhibit hepatitis Cvirus. The compounds are prodrugs of nucleoside monophosphates that,when administered to animals, are intracellularly converted tonucleoside triphosphates. The chirality of the phosphorous atomdetermines the efficiency of the conversion to the nucleosidetriphosphate in the animal. The method disclosed, provides a convergentsynthesis of these single diastereomeric prodrugs which is animprovement over the previously disclosed chromatographic methods ofseparating a single diastereomer from a mixture of diastereomers.

In one embodiment, provided is a method for preparing a compound ofFormula Ia or Ib:

or a pharmaceutically acceptable salt or acid thereof;

wherein:

each R¹, R², R⁷, R²², R²³ or R²⁴ is independently H, OR¹¹, NR¹¹R¹²,C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², C(O)OR¹¹, OC(O)OR¹¹, S(O)_(n)R^(a),S(O)₂NR¹¹R¹², N₃, CN, halogen, (C₁-C₈)alkyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl;

or any two R¹, R², R⁷, R²², R²³ or R²⁴ on adjacent carbon atoms whentaken together are —O(CO)O— or —O(CR¹¹R¹²)O— or when taken together withthe ring carbon atoms to which they are attached form a double bond;

each Base is independently a naturally occurring or modified purine orpyrimidine base linked to the furanose ring through a carbon or nitrogenatom;

each n is independently 0, 1, or 2;

each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

each R^(c) or R^(d) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) and R^(d) are notthe same;

each R⁵ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl or R¹¹ and R¹² taken together with a nitrogen towhich they are both attached form a 3 to 7 membered heterocyclic ringwherein any one carbon atom of said heterocyclic ring can optionally bereplaced with —O—, —S(O)_(n)— or —NR^(a)—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R¹¹ or R¹² is, independently, optionally substituted with one or morehalo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂, C(O)N(R^(a))₂,C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂,C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a);

said method comprising:

(a) providing a compound of Formula II

and

(b) treating the compound of Formula II with a compound of Formula IIIaand a base

thereby forming a compound of Formula Ia or

(c) treating the compound of Formula II with a compound of Formula IIIband a base

thereby forming a compound of Formula Ib;

wherein:

each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said (C₆-C₂₀) aryl orheteroaryl is substituted with one or more halogen, NO₂, or(C₁-C₈)haloalkyl and optionally substituted with one or more CN, N₃,N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a), OC(O)OR^(a),C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, OR^(a) or R^(a)with the proviso that Ar is different from R⁴. In another aspect, Baseis not uracil. In another aspect, Base is not cytosine.

In another aspect, the invention also provides novel intermediatesdisclosed herein which are useful for preparing Formula Ia or FormulaIb.

In other aspects, methods for the synthesis, analysis, separation,isolation, purification, and characterization of the novel intermediatesof this invention are provided.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdescription, structures and formulas. While the invention will bedescribed in conjunction with the enumerated embodiments, it will beunderstood that they are not intended to limit the invention to thoseembodiments. On the contrary, the invention is intended to cover allalternatives, modifications, and equivalents, which may be includedwithin the scope of the present invention.

Typically, the method of for preparing a compound of Formula Ia fromFormula II and Formula IIIa or Formula Ib from Formula II and FormulaIIIb is performed in a suitable solvent. The suitable solvent ispreferably an anhydrous, non-acid, non-hydroxylic solvent. Non-limitingexamples of suitable solvents are ethers, for example, diethyl ether,diisopropyl ether, di t-butyl ether, tetrahydrofuran, dioxane andvarious glyme solvents; dimethylformamide or dimethylacetamide. Apreferred solvent is tetrahydrofuran. The concentration of Formula II inthe solvent is typically about 0.01 to about 1 mole per liter ofsolvent. The method is performed at a temperature of about 0° C. toabout 80° C., more preferably about 20° C. to about 60° C.

The solution of Formula II is typically treated with a hindered base ora non-nucleophilic base. Typical, but non-limiting, examples of hinderedbases are t-butyllithium, sec-isobutyllithium, lithium or sodiumdiisopropylamide and t-butylmagnesium halides. A preferred hindered baseis t-butylmagnesium chloride. Typical, but non-limiting, examples ofnon-nucleophic bases are sodium hydride, potassium hydride, lithiumhydride and calcium hydride. The hindered bases or non-nucleophic basesmay be used as solutions in or as undiluted bases. Preferably, the basesare used as solutions in anhydrous, non-hydroxylic solvents wherein theconcentration of the base in the solvent is about 0.5 to about 3 molesper liter. The molar ratio of base to the compound of Formula II isabout 1:1 to about 3:1, preferably about 1.1:1 to about 1.5:1. Thesolution of the compound of Formula II is typically treated with thebase for about 5 minutes to about two hours, preferably less than 30minutes.

The mixture of the solution of the compound of Formula II and the baseis treated with a compound of Formula IIIa or Formula IIIb for about 30minutes to about 24 hours, preferably about one to about four hours. Themolar ratio of the compound Formula II to the compound of Formula IIIaor Formula IIIb is typically about 1:1 to about 1:4. Preferably, themolar ratio is about 1:1.1 to about 1:2.

In another embodiment of the method for preparing a compound of FormulaIa or Ib or a pharmaceutically salt or ester thereof, Formula Ia isFormula IVa, Formula Ib is Formula IVb and Formula II is Formula V:

In one embodiment of the method for preparing a compound of Formula IVaor IVb from a compound of Formula V, R¹ is H, halogen, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl oroptionally substituted (C₂-C₈)alkynyl. In another aspect of thisembodiment, R¹ is H. In another aspect of this embodiment, R¹ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R¹ is methyl. In another aspect of this embodiment, R¹ isoptionally substituted (C₂-C₈)alkenyl. In another aspect of thisembodiment, R¹ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R¹ is F. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OR¹¹.In another aspect of this embodiment, R² is OH. In another aspect ofthis embodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁷ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, R⁵ is H. In another aspect of this embodiment, one of R^(c)or R^(d) is H. In another aspect of this embodiment, one of R^(c) orR^(d) is H and the other of R^(c) or R^(d) is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴ isoptionally substituted (C₆-C₂₀)aryl. In another aspect of thisembodiment, Ar is optionally substituted nitrophenyl. In another aspectof this embodiment, R²³ is H. In another aspect of this embodiment, R²²is OR¹¹. In another aspect of this embodiment, R²² is OH. In anotheraspect of this embodiment, R²⁴ is N₃. In another aspect of thisembodiment, R²⁴ is H. In another aspect of this embodiment, Base isselected from the group consisting of:

wherein:

each X¹ is independently N or CR¹⁰;

each X² is independently NR¹¹, O, or S(O)_(n);

each R⁸ is independently halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃,NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂,—C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹;

each n is independently 0, 1, or 2;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹),—CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)C₁-C₈)alkyl or R¹¹ and R¹² taken together with a nitrogen towhich they are both attached form a 3 to 7 membered heterocyclic ringwherein any one carbon atom of said heterocyclic ring can optionally bereplaced with —O—, —S(O)_(n)— or —NR^(a)—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹ or R¹² is, independently, optionally substituted withone or more halo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂,C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)),OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a). In anotheraspect, Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, Base is selected from the groupconsisting of:

In another aspect of this embodiment, Base is selected from the groupconsisting of

In another aspect of this embodiment, Base is selected from the groupconsisting of

In another embodiment of the method for preparing a compound of FormulaIVa or IVb from a compound of Formula V, R¹ is H, halogen, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl oroptionally substituted (C₂-C₈)alkynyl; R² is OR¹¹ or halogen; R²² isOR¹¹ and each R⁵, R²³ and R²⁴ is H. In another aspect of thisembodiment, R¹ is H. In another aspect of this embodiment, R¹ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R¹ is methyl. In another aspect of this embodiment, R¹ isoptionally substituted (C₂-C₈)alkenyl. In another aspect of thisembodiment, R¹ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R¹ is F. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment, R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,R⁷ is H. In another aspect of this embodiment, R⁷ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷ isoptionally substituted (C₂-C₈)alkynyl. In another aspect of thisembodiment, R⁷ is CN. In another aspect of this embodiment, one of R^(c)or R^(d) is H. In another aspect of this embodiment, one of R^(c) orR^(d) is H and the other of R^(c) or R^(d) is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴ isoptionally substituted (C₆-C₂₀)aryl. In another aspect of thisembodiment, Ar is optionally substituted nitrophenyl. In another aspectof this embodiment, Base is selected from the group consisting of:

wherein:

each X¹ is independently N or CR¹⁰;

each X² is independently NR¹¹, O, or S(O)_(n);

each R⁸ is independently halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃,NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂,—C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹;

each n is independently 0, 1, or 2;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹),—CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl or R¹¹ and R¹² taken together with a nitrogen towhich they are both attached form a 3 to 7 membered heterocyclic ringwherein any one carbon atom of said heterocyclic ring can optionally bereplaced with —O—, —S(O)_(n)— or —NR^(a)—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹ or R¹² is, independently, optionally substituted withone or more halo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂,C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)),OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a). In anotheraspect, Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, Base is selected from the groupconsisting of:

In another aspect of this embodiment, Base is selected from the groupconsisting of

In another aspect of this embodiment, Base is selected from the groupconsisting of

In another embodiment of the method for preparing a compound of FormulaIVa or IVb from a compound of Formula V, R¹ is H or CH₃; R² is OR¹¹ orhalogen; R⁶ is optionally substituted (C₁-C₈)alkyl; one of R^(c) orR^(d) is H and the other of R^(c) or R^(d) is optionally substituted(C₁-C₈)alkyl; R²² is OR¹¹, and each R⁵, R²³ and R²⁴ is H. In anotheraspect of this embodiment, R¹ is H. In another aspect of thisembodiment, R¹ is CH₃. In another aspect of this embodiment, R² is F. Inanother aspect of this embodiment, R² is OH. In another aspect of thisembodiment, R²² is OH. In another aspect of this embodiment, each R² andR²² is OH. In another aspect of this embodiment, R⁷ is H. In anotheraspect of this embodiment, R⁷ is CH₃. In another aspect of thisembodiment, R⁷ is ethynyl. In another aspect of this embodiment, R⁷ isCN. In another aspect of this embodiment, R⁴ is optionally substituted(C₆-C₂₀)aryl. In another aspect of embodiment, R⁴ is optionallysubstituted phenyl. In another aspect of this embodiment, R⁴ isoptionally substituted napthyl. In another aspect of this embodiment, Aris optionally substituted nitrophenyl. In another aspect of thisembodiment, Base is selected from the group consisting of:

wherein:

each X¹ is independently N or CR¹⁰;

each X² is independently NR¹¹, O, or S(O)_(n);

each R⁸ is independently halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃,NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂,—C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹;

each n is independently 0, 1, or 2;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹),—CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl or R¹¹ and R¹² taken together with a nitrogen towhich they are both attached form a 3 to 7 membered heterocyclic ringwherein any one carbon atom of said heterocyclic ring can optionally bereplaced with —O—, —S(O)_(n)— or —NR^(a)—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹ or R¹² is, independently, optionally substituted withone or more halo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂,C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)),OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a). In anotheraspect, Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, Base is selected from the groupconsisting of:

In another aspect of this embodiment, Base is selected from the groupconsisting of

In another aspect of this embodiment, Base is selected from the groupconsisting of

In another embodiment of the method for preparing a compound of FormulaIVa or IVb from a compound of Formula V, R¹ is H or CH₃; R² is OR¹¹ orhalogen; R⁶ is optionally substituted (C₁-C₈)alkyl; one of R^(c) orR^(d) is H and the other of R^(c) or R^(d) is optionally substituted(C₁-C₈)alkyl; R²² is OR¹¹, each R⁵, R²³ and R²⁴ is H and Base isselected from the group consisting of:

wherein:

each X¹ is independently N or CR¹⁰;

each X² is independently NR¹¹, O, or S(O)_(n);

each R⁸ is independently halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃,NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂,—C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹;

each n is independently 0, 1, or 2;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹),—CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl or R¹¹ and R¹² taken together with a nitrogen towhich they are both attached form a 3 to 7 membered heterocyclic ringwherein any one carbon atom of said heterocyclic ring can optionally bereplaced with —O—, —S(O)_(n)— or —NR^(a)—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹ or R¹² is, independently, optionally substituted withone or more halo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂,C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)),OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a). In anotheraspect Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, R¹ is H. In another aspect of thisembodiment, R¹ is CH₃. In another aspect of this embodiment, R² is F. Inanother aspect of this embodiment, R² is OH. In another aspect of thisembodiment, R²² is OH. In another aspect of this embodiment, each R² andR²² is OH. In another aspect of this embodiment, R⁷ is H. In anotheraspect of this embodiment, R⁷ is CH₃. In another aspect of thisembodiment, R⁷ is ethynyl. In another aspect of this embodiment, R⁷ isCN. In another aspect of this embodiment, R⁴ is optionally substituted(C₆-C₂₀)aryl. In another aspect of embodiment, R⁴ is optionallysubstituted phenyl. In another aspect of this embodiment, R⁴ isoptionally substituted napthyl. In another aspect of this embodiment,one of R^(c) or R^(d) is H and the other of R^(c) or R^(d) is CH₃. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another aspect of this embodiment, Base is

In another embodiment of the method for preparing a compound of FormulaIa or Ib or a pharmaceutically acceptable salt or ester thereof, FormulaIa is Formula VIa, Formula Ib is Formula VIb and Formula II is FormulaVII:

wherein:

each R¹ is independently H, halogen, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionallysubstituted (C₂-C₈)alkynyl;

each R² is independently halogen or OR¹¹;

each R⁵ is H;

each R²² is OR¹¹ and

the remaining variables are defined as for Formulas Ia or Ib or II orIIIa or IIIb.

In one embodiment of the method for preparing a compound of Formula VIaor Formula VIb from a compound of Formula VII, X¹ is CR¹⁰. In anotheraspect of this embodiment, R¹⁰ is H. In another aspect of thisembodiment, R¹ is H. In another aspect of this embodiment, R¹ is F. Inanother aspect of this embodiment, R¹ is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R¹ is methyl. Inanother aspect of this embodiment, R¹ is optionally substituted(C₂-C₈)alkenyl. In another aspect of this embodiment, R¹ is optionallysubstituted ethenyl. In another aspect of this embodiment, R¹ isoptionally substituted (C₂-C₈)alkynyl. In another aspect of thisembodiment, R¹ is optionally substituted ethynyl. In another aspect ofthis embodiment, R² is F. In another aspect of this embodiment, R² isOH. In another aspect of this embodiment R²² is OH. In another aspect ofthis embodiment, each R² and R²² is OH. In another aspect of thisembodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁷ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl.

In another embodiment of the method for preparing a compound of FormulaVIa or Formula VIb from a compound of Formula VII, X¹ is CH, R¹ is H orCH₃ and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,R⁷ is H. In another aspect of this embodiment, R⁷ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷ isCH₃. In another aspect of this embodiment, R⁷ is optionally substituted(C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷ is ethynyl. Inanother aspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, R⁸ is NR¹¹R¹². Inanother aspect of this embodiment, R⁸ is OR¹¹. In another aspect of thisembodiment, R⁸ is NH₂. In another aspect of this embodiment, R⁸ is OH.In another aspect of this embodiment, R⁹ is H. In another aspect of thisembodiment, R⁹ is NR¹¹R¹². In another aspect of this embodiment, R⁹ isOR¹¹. In another aspect of this embodiment, R⁸ is NR¹¹R¹² and R⁹ is H.In another aspect of this embodiment, R⁸ is NR¹¹R¹² and R⁹ is NR¹¹R¹².

In another embodiment of the method for preparing a compound of FormulaVIa or Formula VIb from a compound of Formula VII, X¹ is CH, R¹ is H orCH₃, one of R^(c) or R^(d) is H and R⁷ is CN. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,one of R^(c) or R^(d) is H and the other of R^(c) or R^(d) is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, one ofR^(c) or R^(d) is H and the other of R^(c) or R^(d) is CH₃. In anotheraspect of this embodiment, R⁶ is optionally substituted (C₁-C₈)allyl. Inanother aspect of this embodiment, R⁴ is optionally substituted(C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴ is optionallysubstituted phenyl. In another aspect of this embodiment, Ar isoptionally is NR¹¹R¹². In substituted nitrophenyl. In another aspect ofthis embodiment, R⁸ another aspect of this embodiment, R⁸ is OR¹¹. Inanother aspect of this embodiment, R⁸ is NH₂. In another aspect of thisembodiment, R⁸ is OH. In another aspect of this embodiment, R⁹ is H. Inanother aspect of this embodiment, R⁹ is NR¹¹R¹². In another aspect ofthis embodiment, R⁹ is OR¹¹. In another aspect of this embodiment, R⁸ isNR¹¹R¹² and R⁹ is H. In another aspect of this embodiment, R⁸ is NH₂ andR⁹ is H. In another aspect of this embodiment, R⁸ is NR¹¹R¹² and R⁹ isNR¹¹R¹². In another aspect of this embodiment, R⁸ is NH₂ and R⁹ is NH₂.In another aspect of this embodiment, R⁸ is OH and R⁹ is NH₂.

In another embodiment, provided is a method of preparing a compound ofFormula IIIa or Formula IIIb

wherein:

each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

each R^(c) or R^(d) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) and R^(d) are notthe same;

each R⁵ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R⁴, R⁵ or R⁶ is, independently,optionally substituted with one or more halo, hydroxy, CN, N₃,N(R^(a))₂, NH(R^(a)), NH₂, C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂,OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a),S(O)_(n)R^(a), S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) orR^(a); and

each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said (C₆-C₂₀) aryl orheteroaryl is substituted with one or more halogen, NO₂, or(C₁-C₈)haloalkyl and optionally substituted with one or more CN, N₃,N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a), OC(O)OR^(a),C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, OR^(a) or R^(a)with the proviso that Ar is different from R⁴;

said method comprising:

(d) providing a diastereomeric compound of Formula VIII

and

(e) crystallizing the compound of Formula VIII from a suitable solvent;

thereby forming a pure diasteromer of Formula IIIa or Formula IIIb.

In one embodiment of the method of preparing a compound of Formula IIIaor Formula IIIb, R⁵ is H and one of R^(c) or R^(d) is H. In anotheraspect of this embodiment, one of R^(c) or R^(d) is H and the other ofR^(c) or R^(d) is optionally substituted (C₁-C₈)alkyl.

In another aspect of this embodiment, one of R^(c) or R^(d) is H and theother of R^(c) or R^(d) is CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈) secondary or tertiaryalkyl. In another aspect of this embodiment, R⁴ is optionallysubstituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴ isoptionally substituted phenyl. In another aspect of this embodiment, Aris optionally substituted nitrophenyl. In another aspect of thisembodiment, Ar is optionally substituted para-nitrophenyl. In anotheraspect of this embodiment, the chirality at the carbon directly attachedto R^(c) and R^(d) is S. In another aspect of this embodiment, thechirality at the carbon directly attached to R^(c) and R^(d) is R.

In another embodiment of the method of preparing a compound of FormulaIna or Formula IIIb, R⁵ is H, one of R^(c) or R^(d) is H, R⁶ isoptionally substituted (C₁-C₈)alkyl, and R⁴ is optionally substituted(C₆-C₂₀)aryl. In another aspect of this embodiment, one of R^(c) orR^(d) is H and the other of R^(c) or R^(d) is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, one of R^(c) orR^(d) is H and the other of R^(c) or R^(d) is CH₃. In another aspect ofthis embodiment, R⁶ is optionally substituted (C₁-C₈) secondary ortertiary alkyl. In another aspect of this embodiment, R⁶ is optionallysubstituted 2-propyl. In another aspect of this embodiment, R⁴ isoptionally substituted phenyl. In another aspect of this embodiment, Aris optionally substituted nitrophenyl. In another aspect of thisembodiment, Ar is optionally substituted para-nitrophenyl. In anotheraspect of this embodiment, Ar is para-nitrophenyl. In another aspect ofthis embodiment, the chirality at the carbon directly attached to R^(c)and R^(d) is S. In another aspect of this embodiment, the chirality atthe carbon directly attached to R^(c) and R^(d) is R.

In another embodiment of the method of preparing a compound of FormulaIIIa or Formula IIIb, R⁵ is H, one of R^(c) or R^(d) is H and the otherof R^(c) or R^(d) is optionally substituted (C₁-C₈)alkyl, R⁶ isoptionally substituted (C₁-C₈)alkyl, and R⁴ is optionally substitutedphenyl. In another aspect of this embodiment, one of R^(c) or R^(d) is Hand the other of R^(c) or R^(d) is CH₃. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈) secondary or tertiaryalkyl. In another aspect of this embodiment, R⁶ is optionallysubstituted 2-propyl. In another aspect of this embodiment, R⁴ isphenyl. In another aspect of this embodiment, Ar is optionallysubstituted nitrophenyl. In another aspect of this embodiment, Ar isoptionally substituted para-nitrophenyl. In another aspect of thisembodiment, Ar is para-nitrophenyl. In another aspect of thisembodiment, the chirality at the carbon directly attached to R^(c) andR^(d) is S. In another aspect of this embodiment, the chirality at thecarbon directly attached to R^(c) and R^(d) is R.

In another embodiment of the method of preparing a compound of FormulaIIIa or Formula IIIb, R⁵ is H, one of R^(c) or R^(d) is H and the otherof R^(c) or R^(d) is CH₃, R⁶ is optionally substituted (C₁-C₈)alkyl, andR⁴ is optionally substituted phenyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈) secondary or tertiaryalkyl. In another aspect of this embodiment, R⁶ is optionallysubstituted 2-propyl. In another aspect of this embodiment, R⁶ is2-propyl. In another aspect of this embodiment, R⁴ is phenyl. In anotheraspect of this embodiment, Ar is optionally substituted nitrophenyl. Inanother aspect of this embodiment, Ar is optionally substitutedpara-nitrophenyl. In another aspect of this embodiment, Ar ispara-nitrophenyl. In another aspect of this embodiment, the chirality atthe carbon directly attached to R^(c) and R^(d) is S. In another aspectof this embodiment, the chirality at the carbon directly attached toR^(c) and R^(d) is R.

The diastereomeric mixture of the compound of Formula VIII is resolvedby crystallization of the compound of Formula VIII from a suitablesolvent. Non-limiting examples of suitable solvents are diethyl ether,dipropyl ether, di t-butyl ether, methyl t-butyl ether, C₁-C₆halogenated alkanes, C₅-C₈ hydrocarbon, tetrahydrofuran, toluene,xylene, dioxane and the like. In another embodiment, the compound ofFormula IV is dissolved in a suitable solvent and crystallization isinduced by addition of a C₅-C₈ hydrocarbon or C₅-C₈ cyclic hydrocarbon.In a preferred embodiment, the compound of Formula VIII is dissolved inan ether solvent and crystallization is induced by addition of a C₅-C₈hydrocarbon. In a particularly preferred embodiment, the compound ofFormula VIII is dissolved in diethyl ether and crystallization isinduced by the addition of hexane.

The diastereomeric mixture of the compound of Formula VIII is resolvedby crystallization of the compound of Formula VIII from a suitablesolvent at a temperature of about 80° C. to about −20° C. Preferrably,the temperature is about 30° C. to about −20° C., more preferably aboutambient to −10° C.

The diastereomeric mixture of the compound of Formula VIII is resolvedby crystallization of the compound of Formula VIII from a suitablesolvent wherein the concentration of the compound of Formula VIII insolution is about 25 g to about 1000 g per liter of solvent. Moretypically, the concentration of the compound of Formula VIII is about 50to 500 g per liter of solvent.

The resolution of the diastereomeric mixture of the compound of FormulaVIII by crystallization may be promoted by the addition of seed crystalsof the pure diastereomer. Seed crystals of pure diastereomers may beobtained through purification of the diastereomeric mixture of thecompound of Formula VIII by liquid chromatography, chiral liquidchromatography, high pressure liquid chromatography, or chiral highpressure liquid chromatography such as by the non-limiting methodsdescribed herein.

Typically, the crystallization of the diastereomeric mixture of thecompound of Formula VIII produces a mixture of diastereomers containingat least 60% of a single diastereomer. More typically, the mixtureproduced contains at least 70% of a single diastereomer, most typically,at least 80% of a single diastereomer, preferably at least 90% of asingle diastereomer, and more preferably at least 95% of a singlediastereomer. Higher diastereomeric purity, for example at least 99%diastereomeric purity, may be obtained by one or more subsequentcrystallizations. The yield of crystalline material from a singlecrystallization is typically about 10 to 45%, more typically about20-35%.

In another embodiment, provided is a compound of Formula IIIa or FormulaIIIb

or a salt or ester thereof;

wherein:

each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

each R^(c) or R^(d) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₃)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) and R^(d) are notthe same;

each R⁵ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R⁴, R⁵ or R⁶ is, independently,optionally substituted with one or more halo, hydroxy, CN, N₃,N(R^(a))₂, NH(R^(a)), NH₂, C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂,OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a),S(O)_(n)R^(a), S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) orR^(a); and

each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said (C₆-C₂₀) aryl orheteroaryl is substituted with one or more halogen, NO₂, or(C₁-C₈)haloalkyl and optionally substituted with one or more CN, N₃,N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a), OC(O)OR^(a),C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, OR^(a) or R^(a)with the proviso that Ar is different from R⁴.

In another embodiment of the compound of Formula IIIa or Formula IIIb,R⁵ is H and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶ isoptionally substituted (C₁-C₈) secondary or tertiary alkyl. In anotheraspect of this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, R⁴ is optionally substituted phenyl.In another aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, Ar is optionallysubstituted para-nitrophenyl. In another aspect of this embodiment, thechirality at the carbon directly attached to R^(c) and R^(d) is S. Inanother aspect of this embodiment, the chirality at the carbon directlyattached to R^(c) and R^(d) is R. In another aspect of this embodiment,the moiety

of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of anaturally occurring α-amino acid.

In another embodiment of the compound of Formula IIIa or Formula IIIb,R⁵ is H, one of R^(c) or R^(d) is H, R⁶ is optionally substituted(C₁-C₈)alkyl and R⁴ is optionally substituted (C₆-C₂₀)aryl. In anotheraspect of this embodiment, one of R^(c) or R^(d) is H and the other ofR^(c) or R^(d) is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, one of R^(c) or R^(d) is H and the other of R^(c) orR^(d) is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈) secondary or tertiary alkyl. In another aspect ofthis embodiment, R⁶ is optionally substituted 2-propyl. In anotheraspect of this embodiment, R⁴ is optionally substituted phenyl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, Ar is optionallysubstituted para-nitrophenyl. In another aspect of this embodiment, Aris para-nitrophenyl. In another aspect of this embodiment, the chiralityat the carbon directly attached to R^(c) and R^(d) is S. In anotheraspect of this embodiment, the chirality at the carbon directly attachedto R^(c) and R^(d) is R. In another aspect of this embodiment, themoiety

of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of anaturally occurring α-amino acid.

In another embodiment of the compound of Formula IIIa or Formula IIIb,R⁵ is H, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d) isoptionally substituted (C₁-C₈)alkyl, R⁶ is optionally substituted(C₁-C₈)alkyl and R⁴ is optionally substituted phenyl. In another aspectof this embodiment, one of R^(c) or R^(d) is H and the other of R^(c) orR^(d) is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈) secondary or tertiary alkyl. In another aspect ofthis embodiment, R⁶ is optionally substituted 2-propyl. In anotheraspect of this embodiment, R⁴ is phenyl. In another aspect of thisembodiment, Ar is optionally substituted nitrophenyl. In another aspectof this embodiment, Ar is optionally substituted para-nitrophenyl. Inanother aspect of this embodiment, Ar is para-nitrophenyl. In anotheraspect of this embodiment, the chirality at the carbon directly attachedto R^(c) and R^(d) is S. In another aspect of this embodiment, thechirality at the carbon directly attached to R^(c) and R^(d) is R. Inanother aspect of this embodiment, the moiety

of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of anaturally occurring α-amino acid.

In another embodiment of the compound of Formula IIIa or Formula IIIb,R⁵ is H, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d) isCH₃, R⁶ is optionally substituted (C₁-C₈)alkyl, and R⁴ is optionallysubstituted phenyl. In another aspect of this embodiment, R⁶ isoptionally substituted (C₁-C₈) secondary or tertiary alkyl. In anotheraspect of this embodiment, R⁶ is optionally substituted 2-propyl. Inanother aspect of this embodiment, R⁶ is 2-propyl. In another aspect ofthis embodiment, R⁴ is phenyl. In another aspect of this embodiment, Aris optionally substituted nitrophenyl. In another aspect of thisembodiment, Ar is optionally substituted para-nitrophenyl. In anotheraspect of this embodiment, Ar is para-nitrophenyl. In another aspect ofthis embodiment, the chirality at the carbon directly attached to R^(c)and R^(d) is S. In another aspect of this embodiment, the chirality atthe carbon directly attached to R^(c) and R^(d) is R. In another aspectof this embodiment, the moiety

of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of anaturally occurring α-amino acid.

In another embodiment, provided are compounds of Formula IIIa or FormulaIIIb selected from the group consisting of:

or salts or esters thereof.

In another embodiment, provided is a method of preparing a compound ofFormula VIII

wherein

each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

each R^(c) or R^(d) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) and R^(d) are notthe same;

each R⁵ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl, heteroarylof each R^(c), R^(d), R⁴, R⁵ or R⁶ is, independently, optionallysubstituted with one or more halo, hydroxy, CN, N₃, N(R^(a))₂,NH(R^(a)), NH₂, C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂,OC(O)NH(R^(a)), OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a); and

each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said (C₆-C₂₀) aryl orheteroaryl is substituted with one or more halogen, NO₂, or(C₁-C₈)haloalkyl and optionally substituted with one or more CN, N₃,N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a), OC(O)OR^(a),C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, OR^(a) or R^(a)with the proviso that Ar is different from R⁴;

said method comprising:

(f) providing a chirally pure amino acid ester of Formula IX or a saltthereof

(g) treating the compound of Formula IX with a compound of Formula X inthe presence of a base

wherein each X³ is halogen; and

(h) treating the resulting mixture with ArOH;

thereby forming a compound of Formula VIII.

Typically, the chirally pure amino acid of Formula IX or a salt thereofis dissolved or suspended in a suitable non-nucleophilic solvent.Non-limiting non-nucleophilic solvents include haloalkanes, e.g.,methylene chloride, dichloroethane and ethers, e.g. dioxane,tetrahydrofuran and glymes. Typically, the suspension or solutioncontains about 0.1 to about 5 moles of the compound of Formula IX perliter of solvent.

The suspension or solution of the chirally pure amino acid of Formula IXis treated with a compound of Formula X. Typically, the reaction isconducted at about −20 to about 60° C. The mole ratio of the compound ofFormula IX to the compound of Formula X is about 1:2 to about 2:1,preferably about 1:1. The reaction is conducted in the presence of anon-nucleophilic base. Non-limiting examples of non-nucleophilic basesare tertiary amines, e.g. triethylamine, diisopropylethylamine andtriethylamine; metal hydrides, e.g. LiH, NaH and CaH₂; and nitrogencontaining heterocycles, e.g. pyridine and dimethylaminopyridine. In apreferred embodiment, the base is a tertiary amine such astriethylamine. When the compound of Formula IX is a salt of amono-protic acid, the mole ratio of base to the compound of Formula IXis typically about 2:1. If the compound of Formula IX is a free base,the mole ratio of base to the compound of Formula IX is about 1:1.

The reaction of the compound of Formula IX with the compound of FormulaX may be followed by many conventional means known to those skilled inthe art. Such means include thin-layer chromatography and hplc. When thereaction between the compound Formula IX and the compound of Formula Xis complete, the reaction is treated with a phenolic compound ArOH whereAr is defined as herein. The mole ratio of the compound of Formula X toArOH is about 1.1:1 to about 1:1.1, preferably about 1:1. After theaddition of ArOH, additional base is required, typically enough base toneutralize the acid generated in the reaction. Typically, the additionalbase is a non-nucleophilic base such as described above.

The compound of Formula VIII is isolated by conventional means known tothose skilled in the art. For example, the salt formed in the reactionmay be precipitated from the reaction mixture and the compound ofFormula VIII isolated by evaporation of the solvent followed bycrystallization or chromatography.

In one embodiment of the method of preparing a compound of Formula VIII,R⁵ is H and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶ isoptionally substituted (C₁-C₈) secondary or tertiary alkyl. In anotheraspect of this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, R⁴ is optionally substituted phenyl.In another aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, Ar is optionallysubstituted para-nitrophenyl. In another aspect of this embodiment, thechirality at the carbon directly attached to R^(c) and R^(d) is S. Inanother aspect of this embodiment, the chirality at the carbon directlyattached to R^(c) and R^(d) is R. In another aspect of this embodiment,the compound of Formula IX or salt thereof, is an ester of a naturallyoccurring α-amino acid.

In another embodiment of the method of preparing a compound of FormulaVIII, R⁵ is H, one of R^(c) or R^(d) is H, R⁶ is optionally substituted(C₁-C₈)alkyl, and R⁴ is optionally substituted (C₆-C₂₀)aryl. In anotheraspect of this embodiment, one of R^(c) or R^(d) is H and the other ofR^(c) or R^(d) is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, one of R^(c) or R^(d) is H and the other of R^(c) orR^(d) is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈) secondary or tertiary alkyl. In another aspect ofthis embodiment, R⁶ is optionally substituted 2-propyl. In anotheraspect of this embodiment, R⁴ is optionally substituted phenyl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, Ar is optionallysubstituted para-nitrophenyl. In another aspect of this embodiment, Aris para-nitrophenyl. In another aspect of this embodiment, the chiralityat the carbon directly attached to R^(c) and R^(d) is S. In anotheraspect of this embodiment, the chirality at the carbon directly attachedto R^(c) and R^(d) is R. In another aspect of this embodiment, thecompound of Formula IX or salt thereof, is an ester of a naturallyoccurring α-amino acid.

In another embodiment of the method of preparing a compound of FormulaVIII, R⁵ is H, one of R^(c) or R^(d) is H and the other of R^(c) orR^(d) is optionally substituted (C₁-C₈)alkyl, R⁶ is optionallysubstituted (C₁-C₈)alkyl, and R⁴ is optionally substituted phenyl. Inanother aspect of this embodiment, one of R^(c) or R^(d) is H and theother of R^(c) or R^(d) is CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. Inanother aspect of this embodiment, R⁶ is optionally substituted2-propyl. In another aspect of this embodiment, R⁴ is phenyl. In anotheraspect of this embodiment, Ar is optionally substituted nitrophenyl. Inanother aspect of this embodiment, Ar is optionally substitutedpara-nitrophenyl. In another aspect of this embodiment, Ar ispara-nitrophenyl. In another aspect of this embodiment, the chirality atthe carbon directly attached to R^(c) and R^(d) is S. In another aspectof this embodiment, the chirality at the carbon directly attached toR^(c) and R^(d) is R. In another aspect of this embodiment, the compoundof Formula IX or salt thereof, is an ester of a naturally occurringα-amino acid.

In another embodiment of the method of preparing a compound of FormulaVIII, R⁵ is H, one of R^(c) or R^(d) is H and the other of R^(c) orR^(d) is CH₃, R⁶ is optionally substituted (C₁-C₈)alkyl, and R⁴ isoptionally substituted phenyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. Inanother aspect of this embodiment, R⁶ is optionally substituted2-propyl. In another aspect of this embodiment, R⁶ is 2-propyl. Inanother aspect of this embodiment, R⁴ is phenyl. In another aspect ofthis embodiment, Ar is optionally substituted nitrophenyl. In anotheraspect of this embodiment, Ar is optionally substitutedpara-nitrophenyl. In another aspect of this embodiment, Ar ispara-nitrophenyl. In another aspect of this embodiment, the chirality atthe carbon directly attached to R^(c) and R^(d) is S. In another aspectof this embodiment, the chirality at the carbon directly attached toR^(c) and R^(d) is R. In another aspect of this embodiment, the compoundof Formula IX or salt thereof, is an ester of a naturally occurringα-amino acid.

In another embodiment of the method for preparing a compound of FormulaIa or Ib or a pharmaceutically acceptable salt or ester thereof, FormulaIa is Formula XIa, Formula Ib is Formula XIb and Formula II is FormulaXII:

wherein:

each R¹ is independently H, halogen, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionallysubstituted (C₂-C₈)alkynyl;

each R² is independently halogen or OR¹¹;

each R⁵ is H;

each R²² is OR¹¹ and the remaining variables are defined as for FormulasIa or Ib or II or IIIa or IIIb.

In one embodiment of the method for preparing a compound of Formula XIaor Formula XIb from a compound of Formula XII, X¹ is CR¹⁰. In anotheraspect of this embodiment, R¹⁰ is H. In another aspect of thisembodiment, R¹ is H. In another aspect of this embodiment, R¹ is F. Inanother aspect of this embodiment, R¹ is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R¹ is methyl. Inanother aspect of this embodiment, R¹ is optionally substituted(C₂-C₈)alkenyl. In another aspect of this embodiment, R¹ is optionallysubstituted ethenyl. In another aspect of this embodiment, R¹ isoptionally substituted (C₂-C₈)alkynyl. In another aspect of thisembodiment, R¹ is optionally substituted ethynyl. In another aspect ofthis embodiment, R² is F. In another aspect of this embodiment, R² isOH. In another aspect of this embodiment R²² is OH. In another aspect ofthis embodiment, each R² and R²² is OH. In another aspect of thisembodiment, each R² is F and R²² is OH. In another aspect of thisembodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁷ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl.

In another embodiment of the method for preparing a compound of FormulaXIa or Formula XIb from a compound of Formula XII, X¹ is CH, R¹ is H orCH₃ and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,each R² is F and R²² is OH. In another aspect of this embodiment, R⁷ isH. In another aspect of this embodiment, R⁷ is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R⁷ is CH₃. Inanother aspect of this embodiment, R⁷ is optionally substituted(C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷ is ethynyl. Inanother aspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, R⁸ is NR¹¹R¹². Inanother aspect of this embodiment, R⁸ is OR¹¹. In another aspect of thisembodiment, R⁸ is NH₂. In another aspect of this embodiment, R⁸ is OH.In another aspect of this embodiment, R⁹ is H. In another aspect of thisembodiment, R⁹ is NR¹¹R¹². In another aspect of this embodiment, R⁹ isOR¹¹. In another aspect of this embodiment, R⁸ is NR¹¹R¹² and R⁹ is H.In another aspect of this embodiment, R⁸ is NR¹¹R¹² and R⁹ is NR¹¹R¹².

In another embodiment of the method for preparing a compound of FormulaXIa or Formula XIb from a compound of Formula XII, X¹ is CH, R¹ is H orCH₃, one of R^(c) or R^(d) is H and R⁷ is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,each R² is F and R²² is OH. In another aspect of this embodiment, one ofR^(c) or R^(d) is H and the other of R^(c) or R^(d) is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, one ofR^(c) or R^(d) is H and the other of R^(c) or R^(d) is CH₃. In anotheraspect of this embodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. Inanother aspect of this embodiment, R⁴ is optionally substituted(C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴ is optionallysubstituted phenyl. In another aspect of this embodiment, Ar isoptionally substituted nitrophenyl. In another aspect of thisembodiment, R⁸ is NR¹¹R¹². In another aspect of this embodiment, R⁸ isOR¹¹. In another aspect of this embodiment, R⁸ is NH₂. In another aspectof this embodiment, R⁸ is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹ is NR¹¹R¹². In anotheraspect of this embodiment, R⁹ is OR¹¹. In another aspect of thisembodiment, R⁸ is NR¹¹R¹² and R⁹ is H. In another aspect of thisembodiment, R⁸ is NH₂ and R⁹ is H. In another aspect of this embodiment,R⁸ is NR¹¹R¹² and R⁹ is NR¹¹R¹². In another aspect of this embodiment,R⁸ is NH₂ and R⁹ is NH₂. In another aspect of this embodiment, R⁸ isOR¹¹ and R⁹ is NH₂. In another aspect of this embodiment, R⁸ is OH andR⁹ is NH₂.

In one embodiment of the method for preparing a compound of Formula XIaor Formula XIb from a compound of Formula XII, X¹ is N. In anotheraspect of this embodiment, R¹ is H. In another aspect of thisembodiment, R¹ is F. In another aspect of this embodiment, R¹ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R¹ is methyl. In another aspect of this embodiment, R¹ isoptionally substituted (C₂-C₈)alkenyl. In another aspect of thisembodiment, R¹ is optionally substituted ethenyl. In another aspect ofthis embodiment, R¹ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R¹ is optionally substituted ethynyl. Inanother aspect of this embodiment, R² is F. In another aspect of thisembodiment, R² is OH. In another aspect of this embodiment R²² is OH. Inanother aspect of this embodiment, each R² and R²² is OH. In anotheraspect of this embodiment, each R² is F and R²² is OH. In another aspectof this embodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁷ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl.

In another embodiment of the method for preparing a compound of FormulaXIa or Formula XIb from a compound of Formula XII, X¹ is N, R¹ is H orCH₃ and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,each R² is F and R²² is OH. In another aspect of this embodiment, R⁷ isH. In another aspect of this embodiment, R⁷ is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R⁷ is CH₃. Inanother aspect of this embodiment, R⁷ is optionally substituted(C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷ is ethynyl. Inanother aspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, R⁸ is NR¹¹R¹². Inanother aspect of this embodiment, R⁸ is OR¹¹. In another aspect of thisembodiment, R⁸ is NH₂. In another aspect of this embodiment, R⁸ is OH.In another aspect of this embodiment, R⁹ is H. In another aspect of thisembodiment, R⁹ is NR¹¹R¹².

In another aspect of this embodiment, R⁹ is OR¹¹. In another aspect ofthis embodiment, R⁸ is NR¹¹R¹² and R⁹ is H. In another aspect of thisembodiment, R⁸ is NR¹¹R¹² and R⁹ is NR¹¹R¹².

In another embodiment of the method for preparing a compound of FormulaXIa or Formula XIb from a compound of Formula XII, X¹ is N, R¹ is H orCH₃, one of R^(c) or R^(d) is H and R⁷ is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,each R² is F and R²² is OH. In another aspect of this embodiment, one ofR^(c) or R^(d) is H and the other of R^(c) or R^(d) is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, one ofR^(c) or R^(d) is H and the other of R^(c) or R^(d) is CH₃. In anotheraspect of this embodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. Inanother aspect of this embodiment, R⁴ is optionally substituted(C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴ is optionallysubstituted phenyl. In another aspect of this embodiment, Ar isoptionally substituted nitrophenyl. In another aspect of thisembodiment, R⁸ is NR¹¹R¹². In another aspect of this embodiment, R⁸ isOR¹¹. In another aspect of this embodiment, R⁸ is NH₂. In another aspectof this embodiment, R⁸ is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹ is NR¹¹R¹². In anotheraspect of this embodiment, R⁹ is OR¹¹. In another aspect of thisembodiment, R⁸ is NR¹¹R¹² and R⁹ is H. In another aspect of thisembodiment, R⁸ is NH₂ and R⁹ is H. In another aspect of this embodiment,R⁸ is NR¹¹R¹² and R⁹ is NR¹¹R¹². In another aspect of this embodiment,R⁸ is NH₂ and R⁹ is NH₂. In another aspect of this embodiment, R⁸ isOR¹¹ and R⁹ is NH₂. In another aspect of this embodiment, R⁸ is OH andR⁹ is NH₂.

In another embodiment of the method for preparing a compound of FormulaIa or Ib or a pharmaceutically acceptable salt or ester thereof, FormulaIa is Formula XIIIa, Formula Ib is Formula XIIIb and Formula II isFormula XIV:

wherein:

each R¹ is independently H, halogen, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionallysubstituted (C₂-C₈)alkynyl;

each R² is independently halogen or OR¹¹;

each R⁵ is H;

each R²² is OR¹¹ and

the remaining variables are defined as for Formulas Ia or Ib or II orIIIa or IIIb.

In one embodiment of the method for preparing a compound of FormulaXIIIa or Formula XIIIb from a compound of Formula XIV, X¹ is CR¹⁰. Inanother aspect of this embodiment, R¹⁰ is H. In another aspect of thisembodiment, R¹⁰ is CH₃. In another aspect of this embodiment, R¹ is H.In another aspect of this embodiment, R¹ is F. In another aspect of thisembodiment, R¹ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R¹ is methyl. In another aspect of this embodiment,R¹ is optionally substituted (C₂-C₈)alkenyl. In another aspect of thisembodiment, R¹ is optionally substituted ethenyl. In another aspect ofthis embodiment, R¹ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R¹ is optionally substituted ethynyl. Inanother aspect of this embodiment, R² is F. In another aspect of thisembodiment, R² is OH. In another aspect of this embodiment R²² is OH. Inanother aspect of this embodiment, each R² and R²² is OH. In anotheraspect of this embodiment, each R² is F and R²² is OH. In another aspectof this embodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁷ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl.

In another embodiment of the method for preparing a compound of FormulaXIIIa or Formula XIIIb from a compound of Formula XIV, X¹ is CH, R¹ is Hor CH₃ and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,each R² is F and R²² is OH. In another aspect of this embodiment, R⁷ isH. In another aspect of this embodiment, R⁷ is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R⁷ is CH₃. Inanother aspect of this embodiment, R⁷ is optionally substituted(C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷ is ethynyl. Inanother aspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, R⁸ is NR¹¹R¹². Inanother aspect of this embodiment, R⁸ is OR¹¹. In another aspect of thisembodiment, R⁸ is NH₂. In another aspect of this embodiment, R⁸ is OH.

In another embodiment of the method for preparing a compound of FormulaXIIIa or Formula XIIIb from a compound of Formula XIV, X¹ is CH, R¹ is Hor CH₃, one of R^(c) or R^(d) is H and R⁷ is H. In another aspect ofthis embodiment, R² is F. In another aspect of this embodiment, R² isOH. In another aspect of this embodiment R²² is OH. In another aspect ofthis embodiment, each R² and R²² is OH. In another aspect of thisembodiment, each R² is F and R²² is OH. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴ isoptionally substituted (C₆-C₂₀)aryl. In another aspect of thisembodiment, R⁴ is optionally substituted phenyl. In another aspect ofthis embodiment, Ar is optionally substituted nitrophenyl. In anotheraspect of this embodiment, R⁸ is NR¹¹R¹². In another aspect of thisembodiment, R⁸ is OR¹¹. In another aspect of this embodiment, R⁸ is NH₂.In another aspect of this embodiment, R⁸ is OH.

In one embodiment of the method for preparing a compound of FormulaXIIIa or Formula XIIIb from a compound of Formula XIV, X¹ is CF. Inanother aspect of this embodiment, R¹ is H. In another aspect of thisembodiment, R¹ is F. In another aspect of this embodiment, R¹ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R¹ is methyl. In another aspect of this embodiment, R¹ isoptionally substituted (C₂-C₈)alkenyl. In another aspect of thisembodiment, R¹ is optionally substituted ethenyl. In another aspect ofthis embodiment, R¹ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R¹ is optionally substituted ethynyl. Inanother aspect of this embodiment, R² is F. In another aspect of thisembodiment, R² is OH. In another aspect of this embodiment R²² is OH. Inanother aspect of this embodiment, each R² and R²² is OH. In anotheraspect of this embodiment, each R² is F and R²² is OH. In another aspectof this embodiment, R⁷ is H. In another aspect of this embodiment, R⁷ isoptionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁷ is optionally substituted (C₂-C₈)alkynyl. In anotheraspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl.

In another embodiment of the method for preparing a compound of FormulaXIa or Formula XIb from a compound of Formula XII, X¹ is CF, R¹ is H orCH₃ and one of R^(c) or R^(d) is H. In another aspect of thisembodiment, R² is F. In another aspect of this embodiment, R² is OH. Inanother aspect of this embodiment R²² is OH. In another aspect of thisembodiment, each R² and R²² is OH. In another aspect of this embodiment,each R² is F and R²² is OH. In another aspect of this embodiment, R⁷ isH. In another aspect of this embodiment, R⁷ is optionally substituted(C₁-C₈)alkyl. In another aspect of this embodiment, R⁷ is CH₃. Inanother aspect of this embodiment, R⁷ is optionally substituted(C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷ is ethynyl. Inanother aspect of this embodiment, R⁷ is CN. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is optionally substituted (C₁-C₈)alkyl. In another aspectof this embodiment, R⁴ is optionally substituted (C₆-C₂₀)aryl. Inanother aspect of this embodiment, Ar is optionally substitutednitrophenyl. In another aspect of this embodiment, R⁸ is NR¹¹R¹². Inanother aspect of this embodiment, R⁸ is OR¹¹. In another aspect of thisembodiment, R⁸ is NH₂. In another aspect of this embodiment, R⁸ is OH.

In another embodiment of the method for preparing a compound of FormulaXIIIa or Formula XIIIb from a compound of Formula XIV, X¹ is CF, R¹ is Hor CH₃, one of R^(c) or R^(d) is H and R⁷ is H. In another aspect ofthis embodiment, R² is F. In another aspect of this embodiment, R² isOH. In another aspect of this embodiment R²² is OH. In another aspect ofthis embodiment, each R² and R²² is OH. In another aspect of thisembodiment, each R² is F and R²² is OH. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is optionally substituted (C₁-C₈)alkyl. In another aspect of thisembodiment, one of R^(c) or R^(d) is H and the other of R^(c) or R^(d)is CH₃. In another aspect of this embodiment, R⁶ is optionallysubstituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴ isoptionally substituted (C₆-C₂₀)aryl. In another aspect of thisembodiment, R⁴ is optionally substituted phenyl. In another aspect ofthis embodiment, Ar is optionally substituted nitrophenyl. In anotheraspect of this embodiment, R⁸ is NR¹¹R¹². In another aspect of thisembodiment, R⁸ is OR¹¹. In another aspect of this embodiment, R⁸ is NH₂.In another aspect of this embodiment, R⁸ is OH.

Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

As used herein, “a compound of the invention” or “a compound of FormulaI” means a compound of Formula I or a pharmaceutically acceptable salt,thereof. Similarly, with respect to isolatable intermediates, the phrase“a compound of Formula (number)” means a compound of that formula andpharmaceutically acceptable salts, thereof.

“Alkyl” is hydrocarbon containing normal, secondary, tertiary or cycliccarbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms(i.e, C₁-C₂₀ alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈ alkyl), or 1 to 6carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable alkyl groupsinclude, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃),1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl,—CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃)_(.)

“Alkoxy” means a group having the formula —O-alkyl, in which an alkylgroup, as defined above, is attached to the parent molecule via anoxygen atom. The alkyl portion of an alkoxy group can have 1 to 20carbon atoms (i.e., C₁-C₂₀ alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆ alkoxy). Examples ofsuitable alkoxy groups include, but are not limited to, methoxy (—O—CH₃or —OMe), ethoxy (—OCH₂CH₃ or —OEt), t-butoxy (—O—C(CH₃)₃ or —OtBu) andthe like.

“Haloalkyl” is an alkyl group, as defined above, in which one or morehydrogen atoms of the alkyl group is replaced with a halogen atom. Thealkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e.,C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂ haloalkyl), or 1to 6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable haloalkylgroups include, but are not limited to, —CF₃, —CHF₂, —CFH₂, —CH₂CF₃, andthe like.

“Alkenyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. For example, an alkenyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to 8 carbon atoms (i.e.,C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, ethylene orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to 8 carbon atoms (i.e.,C₂-C₈ alkyne,), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkynyl). Examplesof suitable alkynyl groups include, but are not limited to, acetylenic(—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1-ethyl (—CH(CH₃)—), 1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—),1,2-propyl (—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkene. For example, and alkenylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkenylene radicals include, but are not limited to,1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkyne. For example, an alkynylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkynylene radicals include, but are not limited to, acetylene(—C≡C—), propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡C—).

“Amino” refers generally to a nitrogen radical which can be considered aderivative of ammonia, having the formula —N(X)₂, where each “X” isindependently H, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,etc. The hybridization of the nitrogen is approximately sp^(a).Nonlimiting types of amino include —NH₂, —N(alkyl)₂, —NH(alkyl),—N(carbocyclyl)₂, —NH(carbocyclyl), —N(heterocyclyl)₂,—NH(heterocyclyl), —N(aryl)₂, —NH(aryl), —N(alkyl)(aryl),—N(alkyl)(heterocyclyl), —N(carbocyclyl)(heterocyclyl),—N(aryl)(heteroaryl), —N(alkyl)(heteroaryl), etc. The term “alkylamino”refers to an amino group substituted with at least one alkyl group.Nonlimiting examples of amino groups include —NH₂, —NH(CH₃), —N(CH₃)₂,—NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(phenyl), —N(phenyl)₂, —NH(benzyl),—N(benzyl)₂, etc. Substituted alkylamino refers generally to alkylaminogroups, as defined above, in which at least one substituted alkyl, asdefined herein, is attached to the amino nitrogen atom. Non-limitingexamples of substituted alkylamino includes —NH(alkylene-C(O)—OH),—NH(alkylene-C(O)—O-alkyl), —N(alkylene-C(O)—OH)₂,—N(alkylene-C(O)—O-alkyl)₂, etc.

“Aryl” means an aromatic hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent aromatic ringsystem. For example, an aryl group can have 6 to 20 carbon atoms, 6 to14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include,but are not limited to, radicals derived from benzene (e.g., phenyl),substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms andthe aryl moiety is 6 to 14 carbon atoms.

“Arylalkenyl” refers to an acyclic alkenyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp² carbon atom, is replaced with an arylradical. The aryl portion of the arylalkenyl can include, for example,any of the aryl groups disclosed herein, and the alkenyl portion of thearylalkenyl can include, for example, any of the alkenyl groupsdisclosed herein. The arylalkenyl group can comprise 8 to 20 carbonatoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp carbon atom, is replaced with an arylradical. The aryl portion of the arylalkynyl can include, for example,any of the aryl groups disclosed herein, and the alkynyl portion of thearylalkynyl can include, for example, any of the alkynyl groupsdisclosed herein. The arylalkynyl group can comprise 8 to 20 carbonatoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

The term “substituted” in reference to alkyl, alkylene, aryl, arylalkyl,alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example,“substituted alkyl”, “substituted alkylene”, “substituted aryl”,“substituted arylalkyl”, “substituted heterocyclyl”, and “substitutedcarbocyclyl” means, unless otherwise stated, alkyl, alkylene, aryl,arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R^(b), —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, —NR^(b) ₂, N⁺R^(b) ₃, NR^(b),—CX₃, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHC(═O)R^(b),—OC(═O)R^(b), —NHC(═O)NR^(b) ₂, —S(═O)₂—, —S(═O)₂OH, —S(═O)₂R^(b),—OS(═O)₂OR^(b), —S(═O)₂NR^(b) ₂, —S(═O)R^(b), —OP(═O)(OR^(b))₂,—P(═O)(OR^(b))₂, —P(═O)(O⁻)₂, —P(═O)(OH)₂, —P(O)(OR^(b))(O⁻),—C(═O)R^(b), —C(═O)X, —C(S)R^(b), —C(O)OR^(b), —C(O)O⁻, —C(S)OR^(b),—C(O)SR^(b), —C(S)SR^(b), —C(O)NR^(b) ₂, —C(S)NR^(b) ₂,—C(═NR^(b))NR^(b) ₂, where each X is independently a halogen: F, Cl, Br,or I; and each R^(b) is independently H, alkyl, aryl, arylalkyl, aheterocycle, or a protecting group or prodrug moiety. Alkylene,alkenylene, and alkynylene groups may also be similarly substituted.Unless otherwise indicated, when the term “substituted” is used inconjunction with groups such as arylalkyl, which have two or moremoieties capable of substitution, the substituents can be attached tothe aryl moiety, the alkyl moiety, or both.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.,active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and othermoieties of the compounds of Formula I-XIV should be selected in orderto provide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of Formula I-XIVwhich have such stability are contemplated as falling within the scopeof the present invention.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, or S) the resultingheteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH₃,etc.), an amine (e.g., —NHCH₃, —N(CH₃)₂, etc.), or a thioalkyl group(e.g., —SCH₃). If a non-terminal carbon atom of the alkyl group which isnot attached to the parent molecule is replaced with a heteroatom (e.g.,O, N, or S) the resulting heteroalkyl groups are, respectively, an alkylether (e.g., —CH₂CH₂—O—CH₃, etc.), an alkyl amine (e.g., —CH₂NHCH₃,—CH₂N(CH₃)₂, etc.), or a thioalkyl ether (e.g., —CH₂—S—CH₃). If aterminal carbon atom of the alkyl group is replaced with a heteroatom(e.g., O, N, or S), the resulting heteroalkyl groups are, respectively,a hydroxyalkyl group (e.g., —CH₂CH₂—OH), an aminoalkyl group (e.g.,—CH₂NH₂), or an alkyl thiol group (e.g., —CH₂CH₂—SH). A heteroalkylgroup can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms,or 1 to 6 carbon atoms. A C₁-C₆ heteroalkyl group means a heteroalkylgroup having 1 to 6 carbon atoms.

“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation those heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment ofthe invention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S). The terms “heterocycle” or“heterocyclyl” includes saturated rings, partially unsaturated rings,and aromatic rings (i.e., heteroaromatic rings). Substitutedheterocyclyls include, for example, heterocyclic rings substituted withany of the substituents disclosed herein including carbonyl groups. Anon-limiting example of a carbonyl substituted heterocyclyl is:

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heterocyclyl radical (i.e., aheterocyclyl-alkylene-moiety). Typical heterocyclyl alkyl groupsinclude, but are not limited to heterocyclyl-CH₂—,2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl”portion includes any of the heterocyclyl groups described above,including those described in Principles of Modern HeterocyclicChemistry. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkyl portion of theheterocyclyl alkyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkyl group comprises 3 to 20 carbonatoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbonatoms and the heterocyclyl moiety is 2 to 14 carbon atoms. Examples ofheterocyclylalkyls include by way of example and not limitation5-membered sulfur, oxygen, and/or nitrogen containing heterocycles suchas thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl,oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen,and/or nitrogen containing heterocycles such as piperidinylmethyl,piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl,pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkenyl” refers to an acyclic alkenyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, but also a sp² carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). Theheterocyclyl portion of the heterocyclyl alkenyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkenyl portion ofthe heterocyclyl alkenyl group includes any of the alkenyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkenyl portion of theheterocyclyl alkenyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkenyl group comprises 4 to 20carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenylgroup is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14carbon atoms.

“Heterocyclylalkynyl” refers to an acyclic alkynyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, but also an sp carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety). Theheterocyclyl portion of the heterocyclyl alkynyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkynyl portion ofthe heterocyclyl alkynyl group includes any of the alkynyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkynyl portion of theheterocyclyl alkynyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkynyl group comprises 4 to 20carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynylgroup is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14carbon atoms.

“Heteroaryl” refers to an aromatic heterocyclyl having at least oneheteroatom in the ring. Non-limiting examples of suitable heteroatomswhich can be included in the aromatic ring include oxygen, sulfur, andnitrogen. Non-limiting examples of heteroaryl rings include all of thosearomatic rings listed in the definition of “heterocyclyl”, includingpyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl,thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl,pyridazyl, pyrimidyl, pyrazyl, etc.

The term “purine” or “pyrimidine” base comprises, but is not limited to,adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl,aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-allylaminopurine, N⁶-thioallyl purine, N²-alkylpurines,N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines,C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine,C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine,C⁵-5-iodopyrimidine, C⁶-iodo-pyrimidine, C⁵—Br-vinyl pyrimidine,C⁶—Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine,N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, andpyrazolopyrimidinyl. Purine bases include, but are not limited to,guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.Additional non-classical purine bases includepyrrolo[1,2-f][1,2,4]triazines, imidazo[1,5-f][1,2,4]triazines,imidazo[1,2-f][1,2,4]triazines, and[1,2,4]triazolo[4,3-f][1,2,4]triazines, all of which are optionallysubstituted. The purine and pyrimidine bases of Formula II are linked tothe ribose sugar, or analog thereof, through a nitrogen atom or carbonatom of the base. Functional oxygen and nitrogen groups on the base canbe protected as necessary or desired. Suitable protecting groups arewell known to those skilled in the art, and include, but are not limitedto, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such asacetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

“Carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl),partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) oraromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbonatoms as a bicycle, and up to about 20 carbon atoms as a polycycle.Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fusedrings. Non-limiting examples of monocyclic carbocycles includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examplesof bicyclo carbocycles includes naphthyl, tetrahydronapthalene, anddecaline.

“Carbocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with acarbocyclyl radical as described herein. Typical, but non-limiting,examples of carbocyclylalkyl groups include cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

“Arylheteroalkyl” refers to a heteroalkyl as defined herein, in which ahydrogen atom (which may be attached either to a carbon atom or aheteroatom) has been replaced with an aryl group as defined herein. Thearyl groups may be bonded to a carbon atom of the heteroalkyl group, orto a heteroatom of the heteroalkyl group, provided that the resultingarylheteroalkyl group provides a chemically stable moiety. For example,an arylheteroalkyl group can have the general formulae -alkylene-O-aryl,-alkylene-O-alkylene-aryl, -alkylene-NH-aryl,-alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl,etc. In addition, any of the alkylene moieties in the general formulaeabove can be further substituted with any of the substituents defined orexemplified herein.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in whicha hydrogen atom has been replaced with a heteroaryl group as definedherein. Non-limiting examples of heteroaryl alkyl include—CH₂-pyridinyl, —CH₂-pyrrolyl, —CH₂-oxazolyl, —CH₂-indolyl,—CH₂-isoindolyl, —CH₂-purinyl, —CH₂-furanyl, —CH₂-thienyl,—CH₂-benzofuranyl, —CH₂-benzothiophenyl, —CH₂-carbazolyl,—CH₂-imidazolyl, —CH₂-thiazolyl, —CH₂-isoxazolyl, —CH₂-pyrazolyl,—CH₂-isothiazolyl, —CH₂-quinolyl, —CH₂-isoquinolyl, —CH₂-pyridazyl,—CH₂-pyrimidyl, —CH₂-pyrazyl, —CH(CH₃)-pyridinyl, —CH(CH₃)-pyrrolyl,—CH(CH₃)-oxazolyl, —CH(CH₃)-indolyl, —CH(CH₃)-isoindolyl,—CH(CH₃)-purinyl, —CH(CH₃)-furanyl, —CH(CH₃)-thienyl,—CH(CH₃)-benzofuranyl, —CH(CH₃)-benzothiophenyl, —CH(CH₃)-carbazolyl,—CH(CH₃)-imidazolyl, —CH(CH₃)-thiazolyl, —CH(CH₃)-isoxazolyl,—CH(CH₃)-pyrazolyl, —CH(CH₃)-isothiazolyl, —CH(CH₃)-quinolyl,—CH(CH₃)-isoquinolyl, —CH(CH₃)-pyridazyl, —CH(CH₃)-pyrimidyl,—CH(CH₃)-pyrazyl, etc.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I-XIV (e.g., an optionally substituted arylgroup) refers to a moiety wherein all substiutents are hydrogen orwherein one or more of the hydrogens of the moiety may be replaced bysubstituents such as those listed under the definition of “substituted”.

The term “optionally replaced” in reference to a particular moiety ofthe compound of Formula I-XIV (e.g., the carbon atoms of said(C₁-C₈)alkyl may be optionally replaced by —O—, —S—, or —NR^(a)—) meansthat one or more of the methylene groups of the (C₁-C₈)alkyl may bereplaced by 0, 1, 2, or more of the groups specified (e.g., —O—, —S—, or—NR^(a)—).

The term “non-terminal carbon atom(s)” in reference to an alkyl,alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers tothe carbon atoms in the moiety that intervene between the first carbonatom of the moiety and the last carbon atom in the moiety. Therefore, byway of example and not limitation, in the alkyl moiety—CH₂(C*)H₂(C*)H₂CH₃ or alkylene moiety —CH₂(C*)H₂(C*)H₂CH₂— the C* atomswould be considered to be the non-terminal carbon atoms.

“Linker” or “link” means a chemical moiety comprising a covalent bond ora chain of atoms. Linkers include repeating units of alkyloxy (e.g.polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g.polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide.

The terms such as “oxygen-linked”, “nitrogen-linked”, “carbon-linked”,“sulfur-linked”, or “phosphorous-linked” mean that if a bond between twomoieties can be formed by using more than one type of atom in a moiety,then the bond formed between the moieties is through the atom specified.For example, a nitrogen-linked amino acid would be bonded through anitrogen atom of the amino acid rather than through an oxygen or carbonatom of the amino acid.

Some embodiments of the compounds of Formula I-XIV comprise the moiety

which may comprise a radical of a nitrogen-linked ester of a naturallyoccurring α-amino acid. Examples of naturally occurring amino acidsinclude isoleucine, leucine, lysine, methionine, phenylalanine,threonine, tryptophan, valine, alanine, asparagine, aspartic acid,cysteine, glutamic acid, glutamine, glycine, proline, selenocysteine,serine, tyrosine, arginine, histidine, ornithine and taurine. The estersof these amino acids comprise any of those described for thesubstitutent R⁶, particularly those in which R⁶ is optionallysubstituted (C₁-C₈)alkyl.

Unless otherwise specified, the carbon atoms of the compounds of FormulaI-XIV are intended to have a valence of four. In some chemical structurerepresentations where carbon atoms do not have a sufficient number ofvariables attached to produce a valence of four, the remaining carbonsubstitutents needed to provide a valence of four should be assumed tobe hydrogen. For example,

has the same meaning as

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. The chemical substructure of a protecting group varieswidely. One function of a protecting group is to serve as anintermediate in the synthesis of the parental drug substance. Chemicalprotecting groups and strategies for protection/deprotection are wellknown in the art. See: “Protective Groups in Organic Chemistry”,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protectinggroups are often utilized to mask the reactivity of certain functionalgroups, to assist in the efficiency of desired chemical reactions, e.g.making and breaking chemical bonds in an ordered and planned fashion.Protection of functional groups of a compound alters other physicalproperties besides the reactivity of the protected functional group,such as the polarity, lipophilicity (hydrophobicity), and otherproperties which can be measured by common analytical tools. Chemicallyprotected intermediates may themselves be biologically active orinactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g. alcohols, be physiologicallyacceptable, although in general it is more desirable if the products arepharmacologically innocuous.

“Prodrug moiety” means a labile functional group which separates fromthe active inhibitory compound during metabolism, systemically, inside acell, by hydrolysis, enzymatic cleavage, or by some other process(Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook ofDrug Design and Development (1991), P. Krogsgaard-Larsen and H.Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphases. Prodrug moieties can serve to enhance solubility,absorption and lipophilicity to optimize drug delivery, bioavailabilityand efficacy. A prodrug moiety may include an active metabolite or drugitself

The phosphate group may be a phosphate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis. Alternatively, the prodrug moietymay be sensitive to enzymatic cleavage, such as a lactate ester or aphosphonamidate-ester group.

It is to be noted that all enantiomers, diastereomers, and racemicmixtures, tautomers, polymorphs, pseudopolymorphs of compounds withinthe scope of Formula I-IV and pharmaceutically acceptable salts thereofare embraced by the present invention. All mixtures of such enantiomersand diastereomers are within the scope of the present invention.

A compound of Formula I-XIV and its pharmaceutically acceptable saltsmay exist as different polymorphs or pseudopolymorphs. As used herein,crystalline polymorphism means the ability of a crystalline compound toexist in different crystal structures. The crystalline polymorphism mayresult from differences in crystal packing (packing polymorphism) ordifferences in packing between different conformers of the same molecule(conformational polymorphism). As used herein, crystallinepseudopolymorphism means the ability of a hydrate or solvate of acompound to exist in different crystal structures. The pseudopolymorphsof the instant invention may exist due to differences in crystal packing(packing pseudopolymorphism) or due to differences in packing betweendifferent conformers of the same molecule (conformationalpseudopolymorphism). The instant invention comprises all polymorphs andpseudopolymorphs of the compounds of Formula I-IV and theirpharmaceutically acceptable salts.

A compound of Formula I-XIV and its pharmaceutically acceptable saltsmay also exist as an amorphous solid. As used herein, an amorphous solidis a solid in which there is no long-range order of the positions of theatoms in the solid. This definition applies as well when the crystalsize is two nanometers or less. Additives, including solvents, may beused to create the amorphous forms of the instant invention. The instantinvention comprises all amorphous forms of the compounds of Formula I-IVand their pharmaceutically acceptable salts.

Selected substituents comprising the compounds of Formula I-XIV arepresent to a recursive degree. In this context, “recursive substituent”means that a substituent may recite another instance of itself. Becauseof the recursive nature of such substituents, theoretically, a largenumber of compounds may be present in any given embodiment. One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by way ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis. Recursive substituents are an intended aspect of theinvention. One of ordinary skill in the art of medicinal chemistryunderstands the versatility of such substituents. To the degree thatrecursive substituents are present in an embodiment of the invention,they may recite another instance of themselves, 0, 1, 2, 3, or 4 times.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity).

Any reference to the compounds of the invention described herein alsoincludes a reference to a physiologically acceptable salt thereof.Examples of physiologically acceptable salts of the compounds of theinvention include salts derived from an appropriate base, such as analkali metal or an alkaline earth (for example, Na⁺, Li⁺, K⁺, Ca⁺² andMg⁺²), ammonium and NR^(a) ₄ ⁺ (wherein R^(a) is defined herein).Physiologically acceptable salts of a nitrogen atom or an amino groupinclude (a) acid addition salts formed with inorganic acids, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamicacids, phosphoric acid, nitric acid and the like; (b) salts formed withorganic acids such as, for example, acetic acid, oxalic acid, tartaricacid, succinic acid, maleic acid, fumaric acid, gluconic acid, citricacid, malic acid, ascorbic acid, benzoic acid, isethionic acid,lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamicacid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonicacid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonicacid, malonic acid, sulfosalicylic acid, glycolic acid,2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalicacid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine,glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucineand the like; and (c) salts formed from elemental anions for example,chlorine, bromine, and iodine. Physiologically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NR^(a) ₄ ⁺.

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

Finally, it is to be understood that the compositions herein comprisecompounds of the invention in their un-ionized, as well as zwitterionicform, and combinations with stoichiometric amounts of water as inhydrates.

The compounds of the invention, exemplified by Formula I-XIV have chiralcenters, e.g. chiral carbon or phosphorus atoms. For example, thephosphorous atoms of Formula I-XIV may be chiral because they have fourdifferent substituents. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, reactivities and biologicalproperties. For example, the compounds of Formula I-XIV may have achiral phosphorus atom when phosphorus has four different substitutents,e.g., Formula XIV, where the chirality is R or S. When R^(c) and R^(d)of the amino acid of the phosphoramidate of Formula IV are different,there are two centers of chirality in the molecule leading to potentialdiastereomeric mixtures of compounds, e.g. R,S; S,R; S,S and R,Risomers. Mixtures of diastereomers may be separate under high resolutionanalytical procedures such as electrophoresis, crystallization and/orchromatography. Diastereomeres may have different physical attributessuch as, but not limited to, solubility, chemical stabilities andcrystallinity and may also have different biological properties such as,but not limited to, enzymatic stability, absorption and metabolicstability.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l, D and L, or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with S, (−), or l meaning that the compound islevorotatory while a compound prefixed with R, (+), or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R^(a)” or “R¹”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines,

, indicate the site of covalent bond attachments to the adjoiningsubstructures, groups, moieties, or atoms.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

One skilled in the art will recognize that nucleoside bases such as thepyrrolo[1,2-f][1,2,4]triazine nucleosides can exist in tautomeric forms.For example, but not by way of limitation, structures (a) and (b) canhave equivalent tautomeric forms as shown below:

All possible tautomeric forms of the heterocycles and nucleobases in allof the embodiments disclosed herein are within the scope of theinvention.

The compounds of Formula I-XIV also include molecules that incorporateisotopes of the atoms specified in the particular molecules.Non-limiting examples of these isotopes include D, T, ¹⁴C, ¹³C and ¹⁵N.All such isotopic variations of these molelcules are provided by theinstant invention.

EXAMPLES

Certain abbreviations and acronyms are used in describing theexperimental details. Although most of these would be understood by oneskilled in the art, Table 1 contains a list of many of theseabbreviations and acronyms.

TABLE 1 List of abbreviations and acronyms. Abbreviation Meaning Ac₂Oacetic anhydride AIBN 2,2′-azobis(2-methylpropionitrile) Bn benzyl BnBrbenzylbromide BSA bis(trimethylsilyl)acetamide BzCl benzoyl chloride CDIcarbonyl diimidazole DABCO 1,4-diazabicyclo[2.2.2]octane DBN1,5-diazabicyclo[4.3.0]nonene-5 DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone DBU1,5-diazabicyclo[5.4.0]undecene-5 DCA dichloroacetamide DCCdicyclohexylcarbodiimide DCM dichloromethane DMAP4-dimethylaminopyridine DME 1,2-dimethoxyethane DMTCl dimethoxytritylchloride DMSO dimethylsulfoxide DMTr 4,4′-dimethoxytrityl DMFdimethylformamide EtOAc ethyl acetate ESI electrospray ionization HMDShexamethyldisilazane HPLC High pressure liquid chromatography LDAlithium diisopropylamide LRMS low resolution mass spectrum MCPBAmeta-chloroperbenzoic acid MeCN acetonitrile MeOH methanol MMTC monomethoxytrityl chloride m/z or m/e mass to charge ratio MH⁺ mass plus 1MH⁻ mass minus 1 MsOH methanesulfonic acid MS or ms mass spectrum NBSN-bromosuccinimide rt or r.t. room temperature TBAF tetrabutylammoniumfluoride TMSCl chlorotrimethylsilane TMSBr bromotrimethylsilane TMSIiodotrimethylsilane TEA triethylamine TBA tributylamine TBAPtributylammonium pyrophosphate TBSCl t-butyldimethylsilyl chloride TEABtriethylammonium bicarbonate TFA trifluoroacetic acid TLC or tlc thinlayer chromatography Tr triphenylmethyl Tol 4-methylbenzoyl δ parts permillion down field from tetramethylsilane

Preparation of Compounds

Compound 1a-1f

To a solution of 1a (22.0 g, 54.9 mmol, prepared according to theprocedures described in J.O.C., 2004, 6257) in methanol (300 mL) wasdropwise added acetyl chloride (22 mL) at 0° C. using a dropping funnelover a period of 30 min. and then stirred at room temperature for 16 h.The mixture was concentrated, re-dissolved in ethyl acetate (400 mL),washed with ice-cold 2 N NaOH, and concentrated to dryness, affordingthe crude methyl ether 1b as an oil. MS=437.2 (M+Na⁺).

To a solution of 1b (obtained from the previous step) in methanol (300mL) was added 0.5 M sodium methoxide solution in methanol (20 mL, 10mmol), and stirred for 16 h at room temperature. The reaction wasquenched with 4.0 N HCl solution in dioxane (2.5 mL, 10 mmol). Themixture was then concentrated, affording the crude 1c. MS=201.0 (M+Na⁺).

A mixture of 1c (obtained from the previous step), Tritron X-405 (70% inwater, 6.0 g), 50% KOH (in water, 85 g) in toluene (500 mL) was heatedto reflux with a Dean-Stark trap attached. After 1 h collecting ˜25 mLof water, benzyl chloride (33 g, 260 mmol) was added and continued toreflux with stirring for 16 h. The mixture was then cooled andpartitioned between ethyl acetate (400 mL) and water (300 mL). Theorganic layer was washed with water (300 mL), and concentrated. Theresidue was purified by silica gel column chromatography (˜20%EtOAc/hexanes), affording the methyl ether 1d as an oil (22.0 g, 89% inthree steps). ¹H NMR (300 MHz, CDCl₃): δ 7.3 (m, 15H), 4.5-4.9 (m, 7H),4.37 (m, 1H), 3.87 (d, 1H), 3.56 (m, 2H), 3.52 (s, 3H), 1.40 (s, 3H).

To a solution of 1d (22.0 g, 49.0 mmol) in acetic acid (110 mL) wasadded ˜3 M sulfuric acid (prepared by mixing 4.8 g of concentratedsulfuric acid with 24 mL of water) and stirred at 70° C. for 8 h. Themixture was concentrated to a volume of ˜20 mL, and partitioned betweenethyl acetate and ice-cold 2N NaOH. The ethyl acetate layer wasconcentrated, and purified by silica gel column chromatography (˜35%EtOAc/hexanes), affording 1e as an oil (17.0 g, 80%). MS=457.2 (M+Na⁺).

To a solution of 1e (45 g, 104 mmol) in DMSO (135 mL) was dropwise addedacetic anhydride (90 mL, 815 mmol) at room temperature under argon. Themixture was stirred for 16 h at room temperature, and then poured intoice-water (1 L) while stirring. After ice was completely melted (˜30min), ethyl acetate (˜500 mL) was added. The organic layer wasseparated. This extraction process was repeated three times (3×500 mL).The organic extracts were combined and concentrated. The residue waspurified by silica gel column chromatography (˜20% EtOAc/hexanes),affording 1f as an oil (39 g, 88%). ¹H NMR (300 MHz, DMSO-d₆): δ 7.3 (m,15H), 4.4-4.8 (m, 7H), 4.08 (d, J=7.5 Hz, 1H), 3.75 (dd, J=2, 4, 11.4Hz, 1H), 3.64 (dd, J=5.4, 11.4 Hz, 1H), 1.51 (s, 3H).

To a dry, argon purged round bottom flask (100 mL) were added7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (234 mg, 1.10 mmol)(prepared according to WO2007056170) and anhydrous THF (1.5 mL). TMSCl(276 μL, 2.2 mmol) was then added and the reaction mixture stirred for 2h. The flask was placed into a dry ice/acetone bath (˜−78° C.) and BuLi(2.5 mL, 4.0 mmol, 1.6M in hexanes) was added dropwise. After 1 h, asolution of 1f (432.5 mg, 1.0 mmol) in THF was cooled to 0° C. and thenadded to the reaction flask dropwise. After 1 h of stirring at −78° C.,the flask was warmed to 0° C. and sat. NH₄Cl (5 mL) was added to quenchthe reaction. The organics were extracted using EtOAc (3×10 mL) and thecombined organic layers were dried using MgSO₄. The solvent was removedunder reduced pressure and the crude material was purified using flashchromatography (hexanes/EtOAc). 560 mg (90%) of 2a was isolated as amixture of two anomers. LC/MS=567.2 (M+H⁺). ¹H NMR (300 MHz, CDCl₃): δ7.85 (m, 1H), 7.27 (m, 15H), 7.01 (m, 1H), 6.51 (m, 1H), 4.66 (m, 8H),4.40 (m, 2H), 3.79 (m, 3H), 1.62 (s, 2′-CH₃ from the one anomer), 1.18(s, 2′-CH₃ from the other anomer).

Alternative Procedures for 2a

To a dry, argon purged round bottom flask were added7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (9.6 g, 45 mmol) andanhydrous THF (60 mL). TMSCl (12.4 mL, 99 mmol) was then added and thereaction mixture stirred for 2 h. The flask was placed into a dryice/acetone bath (˜−78° C.) and BuLi (98 mL, 158 mmol, 1.6M in hexanes)was added dropwise. After 1 h, this reaction mixture was added to asolution of 1f (13.0 g, 30 mmol) in THF at −78° C. via cannula. After 2h of stirring at −78° C., the flask was warmed to 0° C. Saturated NH₄Cl(150 mL) was added to quench the reaction. The organics were extractedusing EtOAc (3×100 mL) and the combined organic layers were dried usingMgSO₄. The solvent was removed under reduced pressure and the crudematerial was purified using flash silica gel chromatography(hexanes/EtOAc). 7.5 g (44%) of the desired material 2a was isolated.LC/MS=567.2 (M+H⁺).

To a solution of compound 2a (1 g, 1.77 mmol) in CH₂Cl₂ (20 mL) at 0° C.was added TMSCN (1.4 mL, 10.5 mmol) and BF₃-Et₂O (1 mL, 8.1 mmol). Thereaction mixture was stirred at 0° C. for 0.5 h, then at roomtemperature for additional 0.5 h. The reaction was quenched with NaHCO₃at 0° C., and diluted with CH₃CO₂Et. The organic phase was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel, eluted withCH₃CO₂Et-hexanes (1:1 to 2:1), to give the desired compound 5a (620 mg,61%) as an isomeric mixture. MS=576.1 (M+H⁺).

To a solution of compound 5a (150 mg, 0.26 mmol) in CH₂Cl₂ (4 mL) at−78° C. was added BCl₃ (2 mL, 1M in CH₂Cl₂). The reaction mixture wasstirred at −78° C. for 1 h. The reaction was quenched at −78° C. bydropwise addition of TEA (2 mL) and MeOH (5 mL). The mixture was allowedto warm up to room temperature, evaporated, and co-evaporated with MeOHseveral times. The residue was treated with NaHCO₃ (1 g in 10 mL H₂O),concentrated and purified by HPLC to give the desired product Compound 5(48 mg, 60%). ¹H NMR (300 MHz, D₂O): δ 7.74 (s 1H), 6.76 (d, J=5 Hz,1H), 6.73 (d, J=5 Hz, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.8 (m, 2H), 0.84(s, 3H). MS=305.9 (M+H⁺). The other alpha-anomer was also obtained (9mg, 11%): ¹H NMR (300 MHz, D₂O): δ 7.70 (s 1H), 6.8 (d, J=5 Hz, 1H), 6.7(d, J=5 Hz, 1H), 4.25 (d, J=9 Hz, 1H), 4.07 (m, 1H), 3.85 (m, 1H), 3.7(m, 1H), 1.6 (s, 3H). MS=306.1 (M+H⁺).

Compound A (commercially available, 4.99 g, 23.8 mmol) was dissolved indichloromethane (100 mL) and alanine isopropyl ester hydrochloride (3.98g, 23.8 mmol) was added. The resulting clear solution was cooled −78° C.for 30 min. Triethylamine (6.63 mL, 47.5 mmol) was added dropwise over15 min. The mixture was then allowed to warm to room temperature. After16 h, the solvent was removed by argon stream. The residue wasre-dissolved in MTBE (25 mL) and the insoluble was removed by filtrationunder argon. The filtrate was then condensed by argon stream and thecrude product B was used for the next reaction without furtherpurification. ¹H NMR (300 MHz, CDCl₃): 7.1-7.4 (m, 5H), 5.1 (m, 1H),4.35 (m, 1H), 4.15 (m, 1H), 1.5 (d, 3H), 1.2 (m, 6H). ³¹P NMR (121.4MHz, CDCl₃): δ 7.8 and 8.4 (2 s).

Alanine isopropyl ester hydrochloride (7.95 g, 47.4 mmol) was suspendedin dichloromethane (100 mL). Compound A (10 g, 47.4 mmol) was added.Triethylamine (13.2 mL, 95 mmol) was then dropwise added over a periodof 15 min. (internal reaction temperature; −10° C.˜−3° C.). When thereaction was almost complete (by phosphorous NMR), p-nitrophenol (6.29g, 45.0 mmol) was added as a solid in one portion. To the resultingslurry was added triethylamine (6.28 mL, 45 mmol) over a period of 15min. The mixture was then warmed up to room temperature. When thereaction was complete, MTBE (100 mL) was added. The white precipitatewas removed by filtration. The filter cake was washed with MTBE (3×50mL). The filtrate and washings were combined and concentrated. Theresidue was purified by silica gel column chromatography (0 to 50% ethylacetate/hexanes), affording compound C as a 1:1 ratio of diasteromericmixture (14.1 g, 77%). ¹H NMR (300 MHz, CDCl₃): δ 8.22 (2d, 2H), 7.2-7.4(m, 7H), 5.0 (m, 1H), 4.09 (m, 1H), 3.96 (m, 1H), 1.39 (2d, 3H), 1.22(m, 6H). MS=409.0 (M+H⁺), 407.2 (M−H⁺).

Separation of Two Diatereomers of Compound C

The two diastereomers were separated by chiral column chromatographyunder the following conditions;

Column: Chiralpak IC, 2×25 cm

Solvent system: 70% heptane and 30% isopropanol (IPA)

Flow rate: 6 mL/min.

Loading volume per run: 1.0 mL

Concentration of loading sample: 150 mg/mL in 70% hepane and 30% IPA(S)-compound C: retention time 43 min. ³¹P NMR (161.9 MHz, CDCl₃): δ−2.99 (s). (R)-compound C: retention time 62 min. ³¹P NMR (161.9 MHz,CDCl₃): δ −3.02 (s).

Alternatively, the two diasteromers were separated by crystallizationunder the following procedures;

Compound C was dissolved in diethyl ether (˜10 mL/gram). While stirring,hexanes was then added until the solution became turbid. Seed crystals(˜10 mg/gram of compound C) were added to promote crystallization. Theresulting suspension was gently stirred for 16 h, cooled to ˜0° C.,stirred for an additional 2 h, and filtered to collect the crystallinematerial (recovery yield of the crystalline material 35%-35% Thecrystalline material contains ˜95% of (S)-compound C and ˜5% of(R)-compound C. Re-crystallization afforded 99% diastereomerically pure(S)-isomer.

To a dry, argon purged round-bottom flask were added compound 5 (1.0 g,3.28 mmol) and anhydrous THF (15 mL). The slurry was stirred for 10 min.and the flask was place in a water bath at room temperature.t-Butylmagnesium chloride in THF (1.0 M, 4.91 mL) was dropwise added,and the mixture was stirred for an additional 10 min. A solution of(S)-C (2.68 g, 6.55 mmol) in THF (10 mL) was then added. The flask wasplace in a heating oil bath pre-set at 50° C. and the mixture wasstirred until compound 1 was almost consumed. After ˜2.5 h, the reactionmixture was cooled to room temperature, and methanol (5 mL) was added.Solvents were removed under reduced pressure and the residue waspurified by silica gel column chromatography (70% ethyl acetare/hexanesto remove less polar impurities, 10% methanol/dichloromethane to elutethe product), affording (S)-6 as an off-white solid (1.45 g, 77%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.89 (s, 1H), 7.84 (brs, 2H), 7.36 (t, 2H),7.23 (d, 2H), 7.17 (t, 1H), 6.87 (d, J=4.4 Hz, 1H), 6.74 (d, J=4.4 Hz,1H), 6.02 (dd, 1H), 5.96 (s, 1H), 5.41 (d, 1H), 4.82 (m, 1H), 4.38 (dd,1H), 4.22 (q, 1H), 4.16 (m, 1H), 3.81 (m, 1H), 3.67 (dd, 1H), 1.22 (d,3H), 1.11 (dd, 6H), 0.89 (s, 3H). ³¹P NMR (161.9 MHz, DMSO-d₆): δ 3.99(s). MS=575.0 (M+H⁺), 572.7 (M−H⁺).

To a dry, argon purged round-bottom flask were added compound 7(prepared according to J. Med. Chem., 2005, 48, 5504-5508, 100 mg, 0.38mmol), anhydrous THF (3 mL) and anhydrous NMP (1 mL). The slurry wasstirred for 10 min. and the flask was place in a water bath at roomtemperature. t-Butylmagnesium chloride in THF (1.0 M, 0.76 mL) wasdropwise added, and the mixture was stirred for an additional 10 min. Asolution of (S)-C (313 mg, 0.76 mmol) in THF (2 mL) was then added. Theflask was place in a heating oil bath pre-set at 55° C. and the mixturewas stirred until compound 7 was almost consumed. After ˜2.5 h, thereaction mixture was cooled to room temperature, and methanol (1 mL) wasadded. Solvents were removed under reduced pressure and the residue waspurified by RP-HPLC followed by silica gel column chromatography,affording (S)-8 (130 mg, 65%). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (brs,1H), 7.46 (d, 1H), 7.2-7.4 (m, 5H), 6.28 (d, 1H), 5.70 (dd, 1H), 5.01(m, 1H), 4.49 (m, 2H), 3.8-4.1 (m, 4H), 1.41 (d, 3H), 1.35 (d, 3H), 1.24(d, 6H). ³¹P NMR (162.1 MHz, CDCl₃): δ 3.70 (s). MS=530.0 (M+H⁺), 528.0(M−H⁺). Chiral HPLC retention time (Chiralpak AS-H, 250×4.6 mm 5 micron,100% CH₃CN, 1 mL/min flow rate); 6.5 min vs. 5.2 min for the R-isomer).

Using the general procedures described for the preparation of Compound(S)-C or Compound (R)-C, Compounds 10-24 may be prepared.

Using the general procedures described for the preparation of Compound(S)-6, Compounds 25-38 may be prepared using either Compound (S)-C orCompound (R)-C.

What is claimed is:
 1. A method for preparing a compound of Formula Iaor Ib:

or a pharmaceutically acceptable salt or acid thereof; wherein: each R¹,R², R⁷, R²², R²³ or R²⁴ is independently H, OR¹¹, NR¹¹R¹², C(O)NR¹¹R¹²,—OC(O)NR¹¹R¹², C(O)OR¹¹, OC(O)OR¹¹, S(O)_(n)R^(a), S(O)₂NR¹¹R¹², N₃, CN,halogen, (C₁-C₈)alkyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryl(C₁-C₈)alkyl; or any two R¹, R²,R⁷, R²², R²³ or R²⁴ on adjacent carbon atoms when taken together are—O(CO)O— or —O(CR¹¹R¹²)O— or when taken together with the ring carbonatoms to which they are attached form a double bond; each Base isindependently a naturally occurring or modified purine or pyrimidinebase linked to the furanose ring through a carbon or nitrogen atom;provided that Base is not uracil; each n is independently 0, 1, or 2;each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl,aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl,(C₂-C₂₀)heterocyclyl or heteroaryl; each R^(c) or R^(d) is independentlyH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) andR^(d) are not the same; each R⁵ is independently H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl; each R¹¹ or R¹² isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl,heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl or R¹¹ and R¹²taken together with a nitrogen to which they are both attached form a 3to 7 membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S(O)_(n)— or—NR^(a)—; and wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R¹¹ or R¹² is, independently, optionally substituted with one or morehalo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂, C(O)N(R^(a))₂,C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂,C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a): said methodcomprising: (a) providing a compound of Formula II

and (b) treating the compound of Formula II with a compound of FormulaIIIa and a base

thereby forming a compound of Formula Ia or (c) treating the compound ofFormula II with a compound of Formula IIIb and a base

thereby forming a compound of Formula Ib; wherein: each Ar is a (C₆-C₂₀)aryl or heteroaryl wherein said (C₆-C₂₀) aryl or heteroaryl issubstituted with one or more halogen, NO₂, or (C₁-C₈)haloalkyl andoptionally substituted with with one or more CN, N₃, N(R^(a))₂,C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a), OC(O)OR^(a), C(O)R^(a),OC(O)R^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, OR^(a) or R^(a) with theproviso that Ar is different from R⁴, the method further comprising amethod of preparing a compound of Formula IIIa or Formula IIIb

wherein: each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl; each R^(c) or R^(d) isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-(C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl provided that R^(c) and R^(d) are not the same; each R⁵ isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl; wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl (C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R⁴, R⁵ or R⁶ is, independently,optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^(a))₂NH(R^(a)), NH₂, C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂,OC(O)NH(R^(a)), OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a),S(O)_(n)R^(a)S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a);and each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said (C₆-C₂₀) arylor heteroaryl is substituted with one or more halogen, NO₂, or(C₁-C₈)haloalkyl and optionally substituted with with one or more CN,N₃, N(R^(a))₂ C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a), OC(O)OR^(a),C(O)R^(a), OC(O)R^(a), S(O)_(n) R^(a)S(O)₂N(R^(a))₂, OR^(a) or R^(a)with the proviso that Ar is different from R⁴; said method comprising:(d) providing a diastereomeric compound of Formula VIII

and (e) dissolving the compound of Formula VIII in a suitable solventand inducing crystallization by addition of a C₅-C₈ hydrocarbon or C₅-C₈cyclic hydrocarbon; thereby forming a pure diasteromer of Formula IIIaor Formula IIIb.
 2. The method of claim 1 wherein Formula Ia is FormulaIVa, Formula Ib is Formula IVb and Formula II is Formula V:


3. The method of claim 1 wherein Base is selected from the groupconsisting of:

wherein: each X¹ is independently N or CR¹⁰; each X² is independentlyNR¹¹, O, or S(O)_(n); each R⁸ is independently halogen,NR¹¹R¹²,N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹),—CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹²,—C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl, heteroaryl,—C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹ orSR¹¹; each n is independently 0, 1, or 2; each R⁹ or R¹⁰ isindependently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂,CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,—C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹; each R¹¹ or R¹² isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁ -C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl,heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl or R¹¹ and R¹²taken together with a nitrogen to which they are both attached form a 3to 7 membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S(O)_(n)— or—NR^(a)—; wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹ or R¹² is, independently, optionally substituted withone or more halo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, NO₂,C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)),OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) or R^(a); and providedthat Base is not uracil.
 4. The method of claim 3 wherein Base isselected from the group consisting of:


5. The method of claim 1 wherein Formula Ia is Formula VIa, Formula Ibis Formula VIb and Formula II is Formula VII:


6. The method of claim 1 wherein Formula Ia is Formula XIa, Formula Ibis Formula XIb and Formula II is Formula XII:

wherein: each R^(l) is independently H, halogen, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionallysubstituted (C₂-C₈)alkynyl; each R² is independently halogen or OR¹¹;each R⁵ is H; and each R²² is OR¹¹.
 7. The method of claim 1 whereinFormula Ia is Formula XIIIa, Formula Ib is Formula XIIIb and Formula IIis Formula XIV:

wherein: each R¹ is independently H, halogen, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionallysubstituted (C₂-C₈)alkynyl; each R² is independently halogen or OR¹¹;each R⁵ is H; and each R²² is OR¹¹.
 8. The method of claim 1 wherein R¹is H, halogen, optionally substituted (C₁-C₈)alkyl, optionallysubstituted (C₂-C₈)alkenyl or optionally substituted (C₂-C₈)alkynyl. 9.The method of claim 8 wherein R¹ is H, CH₃ or F.
 10. The method of claim1 wherein each R⁵, R²³ and R²⁴ is H.
 11. The method of claim 1 whereinone of R^(c) or R^(d) is H and the other of R^(c) or R^(d) is optionallysubstituted (C₁-C₈)alkyl.
 12. The method of claim 1 wherein R⁶ isoptionally substituted (C₁-C₈)alkyl.
 13. The method of claim 1 whereinR⁸ is NR¹¹R¹² or OR¹¹.
 14. The method of claim 13 wherein R⁹ is H orNR¹¹R¹².
 15. The method of claim 1 wherein when R⁸ or R⁹ is OR¹¹ orNR¹¹R¹² then each R¹¹ and R¹² of said OR¹¹ or NR¹¹R¹² is H.
 16. Themethod of claim 14 wherein R⁸ is NH₂ and R⁹ is H.
 17. The method ofclaim 1 wherein R⁴ is optionally substituted (C₆-C₂₀)aryl.
 18. Themethod of claim 1 wherein the compound of Formula VIII is dissolved inan ether solvent and the crystallization is induced by addition of aC₅-C₈ hydrocarbon.
 19. The method of claim 1 wherein the compound ofFormula VIII is dissolved in diethyl ether or methyl-t-butyl ether andcrystallization is induced by the addition of hexane.
 20. The method ofclaim 19 wherein the compound of Formula VIII is dissolved in diethylether and crystallization is induced by the addition of hexane.
 21. Themethod of claim 1 further comprising a method of preparing a compound ofFormula VIII

wherein: each R^(a), R⁴ or R⁶ is independently (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁ -C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl; each R^(c) or R^(d) isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl provided that R^(c) and R^(d) are not the same; each R⁵ isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl; wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl of each R^(c), R^(d), R⁴, R⁵ or R⁶ is, independently,optionally substituted with one or more halo, hydroxy, CN, N₃,N(R^(a))₂, NH(R^(a)), NH₂, C(O)N(R^(a))₂, C(O)NH(R^(a)), C(O)NH₂,OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂, C(O)OR^(a), OC(O)OR^(a),S(O)_(n)R^(a), S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)), S(O)₂NH₂, OR^(a) orR^(a); and each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said(C₆-C₂₀) aryl or heteroaryl is substituted with one or more halogen,NO₂, or (C₁-C₈)haloalkyl and optionally substituted with with one ormore CN, N₃, N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂, C(O)OR^(a),OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂,OR^(a) or R^(a) with the proviso that Ar is different from R⁴; saidmethod comprising: (f) providing a chirally pure amino acid ester ofFormula IX or a salt thereof

(g) treating the compound of Formula IX with a compound of Formula X inthe presence of a base

wherein each X³ is halogen; and (h) treating the resulting mixture withArOH; thereby forming a compound of Formula VIII.
 22. A method ofpreparing a compound of Formula IIIa or Formula IIIb

or a salt or ester thereof, wherein: each R^(a), R⁴ or R⁶ isindependently (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl; each R^(c) or R^(d) is independently H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) andR^(d) are not the same; each R⁵ is independently H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl; wherein each(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁ -C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^(c), R^(d),R⁴, R⁵ or R⁶ is, independently, optionally substituted with one or morehalo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, C(O)N(R^(a))₂,C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂,C(O)OR^(a), OC(O)OR^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)),S(O)₂NH₂, OR^(a) or R^(a); and each Ar is a (C₆-C₂₀) aryl or heteroarylwherein said (C₆-C₂₀) aryl or heteroaryl is substituted with one or morehalogen, NO₂, or (C₁-C₈)haloalkyl and optionally substituted with withone or more CN, N₃, N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂,C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, OR^(a) or R^(a) with the proviso that Ar is differentfrom R⁴; said method comprising: (d) providing a diastereomeric compoundof Formula VIII

and (e) dissolving the compound of Formula VIII in a suitable solventand inducing crystallization by addition of a C₅-C₈ hydrocarbon or C₅-C₈cyclic hydrocarbon; thereby forming a pure diasteromer of Formula IIIaor Formula IIIb.
 23. The method of claim 22 wherein the compound ofFormula VIII is dissolved in an ether solvent and the crystallization isinduced by addition of a C₅-C₈ hydrocarbon.
 24. The method of claim 23wherein the compound of Formula VIII is dissolved in diethyl ether ormethyl-t-butyl ether and crystallization is induced by the addition ofhexane.
 25. The method of claim 24 wherein the compound of Formula VIIIis dissolved in diethyl ether and crystallization is induced by theaddition of hexane.
 26. The method of claim 22 further comprising amethod of preparing a compound of Formula VIII

or a salt or ester thereof, wherein each R^(a), R⁴ or R⁶ isindependently (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl,heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl orheteroaryl; each R^(c) or R^(d) is independently H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl provided that R^(c) andR^(d) are not the same; each R⁵ is independently H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl; wherein each(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl,(C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl,(C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^(c), R^(d),R⁴, R⁵ or R⁶ is, independently, optionally substituted with one or morehalo, hydroxy, CN, N₃, N(R^(a))₂, NH(R^(a)), NH₂, C(O)N(R^(a))₂,C(O)NH(R^(a)), C(O)NH₂, OC(O)N(R^(a))₂, OC(O)NH(R^(a)), OC(O)NH₂,C(O)OR^(a), OC(O)OR^(a), S(O)_(n)R^(a), S(O)₂N(R^(a))₂, S(O)₂NH(R^(a)),S(O)₂NH₂, OR^(a) or R^(a); and each Ar is a (C₆-C₂₀) aryl or heteroarylwherein said (C₆-C₂₀) aryl or heteroaryl is substituted with one or morehalogen, NO₂, or (C₁-C₈)haloalkyl and optionally substituted with withone or more CN, N₃, N(R^(a))₂, C(O)N(R^(a))₂, OC(O)N(R^(a))₂,C(O)OR^(a), OC(O)OR^(a), C(O)R^(a), OC(O)R^(a), S(O)_(n)R^(a),S(O)₂N(R^(a))₂, OR^(a) or R^(a) with the proviso that Ar is differentfrom R⁴; said method comprising: (f) providing a chirally pure aminoacid ester of Formula IX or a salt thereof

(g) treating the compound of Formula IX with a compound of Formula X inthe presence of a base

wherein each X³ is halogen; and (h) treating the resulting mixture withArOH; thereby forming a compound of Formula VIII.
 27. The method ofclaim 22 wherein R⁵ is H and one of R^(c) or R^(d) is H.
 28. The methodof claim 22 wherein R⁶ is optionally substituted (C₁-C₈)alkyl and R⁴ isoptionally substituted (C₆-C₂₀)aryl.
 29. The method of claim 22 whereinR⁴ is optionally substituted phenyl.
 30. The method of claim 22 whereinone of R^(c) or R^(d) is H and the other of R^(c) or R^(d) is CH₃. 31.The method of claim 22 wherein Ar is optionally substitutedpara-nitrophenyl.
 32. The method of claim 22 wherein the chirality atthe carbon directly attached to R^(c) and R^(d) is S.
 33. The method ofclaim 22 wherein the chirality at the carbon directly attached to R^(c)and R^(d) is R.
 34. The method of claim 22 wherein the compound isselected from the group consisting of

or salts or esters thereof.